Collagenase-mediated extracellular matrix targeting for enhanced drug penetration and therapeutic efficacy in nanoscale delivery systems for cancer therapy | Journal of Nanobiotechnology

  • Sleeboom JJF, van Tienderen GS, Schenke-Layland K, van der Laan LJW, Khalil AA, Verstegen MMA. The extracellular matrix as hallmark of cancer and metastasis: from biomechanics to therapeutic targets. Sci Transl Med. 2024. https://doi.org/10.1126/scitranslmed.adg3840.

    Article 
    PubMed 

    Google Scholar 

  • Paolillo M, Schinelli S. Extracellular matrix alterations in metastatic processes. Int J Mol Sci. 2019;20:4947. https://doi.org/10.3390/ijms20194947.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Glabman RA, Choyke PL, Sato N. Cancer-associated fibroblasts: tumorigenicity and targeting for cancer therapy. Cancers (Basel). 2022;14:3906. https://doi.org/10.3390/cancers14163906.

    Article 
    PubMed 

    Google Scholar 

  • Roma-Rodrigues C, Mendes R, Baptista PV, Fernandes AR. Targeting tumor microenvironment for cancer therapy. Int J Mol Sci. 2019;20:840. https://doi.org/10.3390/ijms20040840.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kai F, Drain AP, Weaver VM. The extracellular matrix modulates the metastatic journey. Dev Cell. 2019;49:332–46. https://doi.org/10.1016/j.devcel.2019.03.026.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yuan Z, Li Y, Zhang S, Wang X, Dou H, Yu X, et al. Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Mol Cancer. 2023;22:48. https://doi.org/10.1186/s12943-023-01744-8.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xiong J, Xiao R, Zhao J, Zhao Q, Luo M, Li F, et al. Matrix stiffness affects tumor-associated macrophage functional polarization and its potential in tumor therapy. J Transl Med. 2024;22:85. https://doi.org/10.1186/s12967-023-04810-3.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Deng B, Zhao Z, Kong W, Han C, Shen X, Zhou C. Biological role of matrix stiffness in tumor growth and treatment. J Transl Med. 2022;20:540. https://doi.org/10.1186/s12967-022-03768-y.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zeltz C, Primac I, Erusappan P, Alam J, Noel A, Gullberg D. Cancer-associated fibroblasts in desmoplastic tumors: emerging role of integrins. Semin Cancer Biol. 2020;62:166–81. https://doi.org/10.1016/j.semcancer.2019.08.004.

    Article 
    PubMed 

    Google Scholar 

  • De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017;17:457–74. https://doi.org/10.1038/nrc.2017.51.

    Article 
    PubMed 

    Google Scholar 

  • Kugeratski FG, Atkinson SJ, Neilson LJ, Lilla S, Knight JRP, Serneels J, et al. Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Sci Signal. 2019;12:eaan8247. https://doi.org/10.1126/scisignal.aan8247.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dzobo K, Dandara C. The extracellular matrix: its composition, function, remodeling, and role in tumorigenesis. Biomimetics. 2023;8:146. https://doi.org/10.3390/biomimetics8020146.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK. Extracellular matrix structure. Adv Drug Deliv Rev. 2016;97:4–27. https://doi.org/10.1016/j.addr.2015.11.001.

    Article 
    PubMed 

    Google Scholar 

  • He X, Yang Y, Li L, Zhang P, Guo H, Liu N, et al. Engineering extracellular matrix to improve drug delivery for cancer therapy. Drug Discov Today. 2020;25:1727–34. https://doi.org/10.1016/j.drudis.2020.06.029.

    Article 
    PubMed 

    Google Scholar 

  • Gouarderes S, Mingotaud A-F, Vicendo P, Gibot L. Vascular and extracellular matrix remodeling by physical approaches to improve drug delivery at the tumor site. Expert Opin Drug Deliv. 2020;17:1703–26. https://doi.org/10.1080/17425247.2020.1814735.

    Article 
    PubMed 

    Google Scholar 

  • Morin PJ. Drug resistance and the microenvironment: nature and nurture. Drug Resist Updat. 2003;6:169–72. https://doi.org/10.1016/S1368-7646(03)00059-1.

    Article 
    PubMed 

    Google Scholar 

  • Stylianopoulos T, Munn LL, Jain RK. Reengineering the physical microenvironment of tumors to improve drug delivery and efficacy: from mathematical modeling to bench to bedside. Trends Cancer. 2018;4:292–319. https://doi.org/10.1016/j.trecan.2018.02.005.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Diener B, Carrick L, Berk RS. In vivo studies with collagenase from Pseudomonas aeruginosa. Infect Immun. 1973;7:212–7. https://doi.org/10.1128/iai.7.2.212-217.1973.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lammers T. Nanomedicine tumor targeting. Adv Mater. 2024. https://doi.org/10.1002/adma.202312169.

    Article 
    PubMed 

    Google Scholar 

  • Hebert JD, Myers SA, Naba A, Abbruzzese G, Lamar JM, Carr SA, et al. Proteomic profiling of the ECM of xenograft breast cancer metastases in different organs reveals distinct metastatic niches. Cancer Res. 2020;80:1475–85. https://doi.org/10.1158/0008-5472.CAN-19-2961.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Naba A, Clauser KR, Lamar JM, Carr SA, Hynes RO. Extracellular matrix signatures of human mammary carcinoma identify novel metastasis promoters. Elife. 2014;3:e01308. https://doi.org/10.7554/eLife.01308.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mai Z, Lin Y, Lin P, Zhao X, Cui L. Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy. Cell Death Dis. 2024;15:307. https://doi.org/10.1038/s41419-024-06697-4.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cheng PSW, Zaccaria M, Biffi G. Functional heterogeneity of fibroblasts in primary tumors and metastases. Trends Cancer. 2025;11:135–53. https://doi.org/10.1016/j.trecan.2024.11.005.

    Article 
    PubMed 

    Google Scholar 

  • Barbazán J, Matic Vignjevic D. Cancer associated fibroblasts: is the force the path to the dark side? Curr Opin Cell Biol. 2019;56:71–9. https://doi.org/10.1016/j.ceb.2018.09.002.

    Article 
    PubMed 

    Google Scholar 

  • Chen Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol. 2021;18:792–804. https://doi.org/10.1038/s41571-021-00546-5.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Margadant C, Sonnenberg A. Integrin–TGF-β crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 2010;11:97–105. https://doi.org/10.1038/embor.2009.276.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Strating E, Verhagen MP, Wensink E, Dünnebach E, Wijler L, Aranguren I, et al. Co-cultures of colon cancer cells and cancer-associated fibroblasts recapitulate the aggressive features of mesenchymal-like colon cancer. Front Immunol. 2023;14:1053920. https://doi.org/10.3389/fimmu.2023.1053920.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang Y, Sun H, Yu H, Wang L, Gao C, Mei H, et al. Tumor-associated-fibrosis and active collagen-CD44 axis characterize a poor-prognosis subtype of gastric cancer and contribute to tumor immunosuppression. J Transl Med. 2025;23:123. https://doi.org/10.1186/s12967-025-06070-9.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bigos KJA, Quiles CG, Lunj S, Smith DJ, Krause M, Troost EGC, et al. Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours. Front Oncol. 2024;14:1331355. https://doi.org/10.3389/fonc.2024.1331355.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rubinstein-Achiasaf L, Morein D, Ben-Yaakov H, Liubomirski Y, Meshel T, Elbaz E, et al. Persistent inflammatory stimulation drives the conversion of MSCs to inflammatory CAFs that promote pro-metastatic characteristics in breast cancer cells. Cancers (Basel). 2021;13:1472. https://doi.org/10.3390/cancers13061472.

    Article 
    PubMed 

    Google Scholar 

  • Cox TR. The matrix in cancer. Nat Rev Cancer. 2021. https://doi.org/10.1038/s41568-020-00329-7.

    Article 
    PubMed 

    Google Scholar 

  • Connor A, Gallinger S. Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data. Nat Rev Cancer. 2022;22:131–42. https://doi.org/10.1038/s41568-021-00418-1.

    Article 
    PubMed 

    Google Scholar 

  • Zhang J, Miao L, Guo S, Zhang Y, Zhang L, Satterlee A, et al. Synergistic anti-tumor effects of combined gemcitabine and cisplatin nanoparticles in a stroma-rich bladder carcinoma model. J Control Release. 2014;182:90–6. https://doi.org/10.1016/j.jconrel.2014.03.016.

    Article 
    PubMed 

    Google Scholar 

  • Cabral H, Matsumoto Y, Mizuno K, Chen Q, Murakami M, Kimura M, et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat Nanotechnol. 2011;6:815–23. https://doi.org/10.1038/nnano.2011.166.

    Article 
    PubMed 

    Google Scholar 

  • Stylianopoulos T, Jain RK. Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc Natl Acad Sci U S A. 2013;110:18632–7. https://doi.org/10.1073/pnas.1318415110.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li Q, Yang C, Li J, Wang R, Min J, Song Y, et al. The type I collagen paradox in PDAC progression: microenvironmental protector turned tumor accomplice. J Transl Med. 2025;23:744. https://doi.org/10.1186/s12967-025-06778-8.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Masamune A, Kikuta K, Watanabe T, Satoh K, Hirota M, Hamada S, et al. Fibrinogen induces cytokine and collagen production in pancreatic stellate cells. Gut. 2009;58:550–9. https://doi.org/10.1136/gut.2008.154401.

    Article 
    PubMed 

    Google Scholar 

  • Bulle A, Lim K-H. Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer. Signal Transduct Target Ther. 2020;5:1–12. https://doi.org/10.1038/s41392-020-00341-1.

    Article 

    Google Scholar 

  • Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res. 2012;18:4266–76. https://doi.org/10.1158/1078-0432.CCR-11-3114.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Karousou E, D’Angelo ML, Kouvidi K, Vigetti D, Viola M, Nikitovic D, et al. Collagen VI and Hyaluronan: The Common Role in Breast Cancer. Biomed Res Int. 2014;2014:606458. https://doi.org/10.1155/2014/606458.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fang M, Yuan J, Peng C, Li Y. Collagen as a double-edged sword in tumor progression. Tumor Biol. 2014;35:2871–82. https://doi.org/10.1007/s13277-013-1511-7.

    Article 

    Google Scholar 

  • Yu S, Zhang C, Xie K-P. Therapeutic resistance of pancreatic cancer: roadmap to its reversal. Biochimica et Biophysica Acta (BBA). 2021;1875:188461. https://doi.org/10.1016/j.bbcan.2020.188461.

    Article 

    Google Scholar 

  • Hosein AN, Brekken RA, Maitra A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol. 2020;17:487–505. https://doi.org/10.1038/s41575-020-0300-1.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Heydari S, Tajik F, Safaei S, Kamani F, Karami B, Dorafshan S, et al. The association between tumor-stromal collagen features and the clinical outcomes of patients with breast cancer: a systematic review. Breast Cancer Res. 2025;27:69. https://doi.org/10.1186/s13058-025-02017-6.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hruska AM, Yang H, Leggett SE, Guo M, Wong IY. Mechanobiology of Collective Cell Migration in 3D Microenvironments. 2023; 1–32. https://doi.org/10.1007/978-3-031-22802-5_1

  • Henke E, Nandigama R, Ergun S. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy. Front Mol Biosci. 2020;6:160. https://doi.org/10.3389/fmolb.2019.00160.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 2000;60:2497–503.

    PubMed 

    Google Scholar 

  • Sykes EA, Dai Q, Sarsons CD, Chen J, Rocheleau JV, Hwang DM, et al. Tailoring nanoparticle designs to target cancer based on tumor pathophysiology. Proc Natl Acad Sci U S A. 2016;113:E1142-51. https://doi.org/10.1073/pnas.1521265113.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pluen A, Boucher Y, Ramanujan S, McKee TD, Gohongi T, di Tomaso E, et al. Role of tumor–host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proc Natl Acad Sci U S A. 2001;98:4628–33. https://doi.org/10.1073/pnas.081626898.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nichols JW, Bae YH. Odyssey of a cancer nanoparticle: from injection site to site of action. Nano Today. 2012;7:606–18. https://doi.org/10.1016/j.nantod.2012.10.010.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ramanujan S, Pluen A, McKee TD, Brown EB, Boucher Y, Jain RK. Diffusion and convection in collagen gels: implications for transport in the tumor interstitium. Biophys J. 2002;83:1650. https://doi.org/10.1016/S0006-3495(02)73933-7.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Erikson A, Andersen HN, Naess SN, Sikorski P, Davies CdeL. Physical and chemical modifications of collagen gels: impact on diffusion. Biopolymers. 2008;89:135–43. https://doi.org/10.1002/bip.20874.

    Article 
    PubMed 

    Google Scholar 

  • Chauhan VP, Lanning RM, Diop-Frimpong B, Mok W, Brown EB, Padera TP, et al. Multiscale measurements distinguish cellular and interstitial hindrances to diffusion in vivo. Biophys J. 2009;97:330–6. https://doi.org/10.1016/j.bpj.2009.03.064.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • He X, Yang Y, Han Y, Cao C, Zhang Z, Li L, et al. Extracellular matrix physical properties govern the diffusion of nanoparticles in tumor microenvironment. Proc Natl Acad Sci U S A. 2023. https://doi.org/10.1073/pnas.2209260120.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ, Rettig WJ. Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts*. J Biol Chem. 1999;274:36505–12. https://doi.org/10.1074/jbc.274.51.36505.

    Article 
    PubMed 

    Google Scholar 

  • Santos AM, Jung J, Aziz N, Kissil JL, Puré E. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest. 2009;119:3613–25. https://doi.org/10.1172/JCI38988.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Murakami M, Ernsting MJ, Undzys E, Holwell N, Foltz WD, Li S-D. Docetaxel conjugate nanoparticles that target α-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis. Cancer Res. 2013;73:4862–71. https://doi.org/10.1158/0008-5472.CAN-13-0062.

    Article 
    PubMed 

    Google Scholar 

  • Teng F, Tian W-Y, Wang Y-M, Zhang Y-F, Guo F, Zhao J, et al. Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis. J Hematol Oncol. 2016;9:8. https://doi.org/10.1186/s13045-015-0231-4.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500–4. https://doi.org/10.1038/nature11183.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Duluc C, Moatassim-Billah S, Chalabi-Dchar M, Perraud A, Samain R, Breibach F, et al. Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance. EMBO Mol Med. 2015;7:735–53. https://doi.org/10.15252/emmm.201404346.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Huang S, Rui F, Jun X, Shenghong Q, Huan Z, Jun D, et al. Evaluation of the tumor targeting of a FAPα-based doxorubicin prodrug. J Drug Target. 2011;19:487–96. https://doi.org/10.3109/1061186X.2010.511225.

    Article 
    PubMed 

    Google Scholar 

  • Akinboye ES, Brennen WN, Rosen DM, Bakare O, Denmeade SR. Iterative design of emetine-based prodrug targeting fibroblast activation protein (FAP) and dipeptidyl peptidase IV DPPIV using a tandem enzymatic activation strategy. Prostate. 2016;76:703–14. https://doi.org/10.1002/pros.23162.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Eikenes L, Bruland ØS, Brekken C, Davies CDL. Collagenase increases the transcapillary pressure gradient and improves the uptake and distribution of monoclonal antibodies in human osteosarcoma xenografts. Cancer Res. 2004;64:4768–73. https://doi.org/10.1158/0008-5472.CAN-03-1472.

    Article 
    PubMed 

    Google Scholar 

  • Kato M, Hattori Y, Kubo M, Maitani Y. Collagenase-1 injection improved tumor distribution and gene expression of cationic lipoplex. Int J Pharm. 2012;423:428–34. https://doi.org/10.1016/j.ijpharm.2011.12.015.

    Article 
    PubMed 

    Google Scholar 

  • McKee TD, Grandi P, Mok W, Alexandrakis G, Insin N, Zimmer JP, et al. Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic Herpes simplex virus vector. Cancer Res. 2006;66:2509–13. https://doi.org/10.1158/0008-5472.CAN-05-2242.

    Article 
    PubMed 

    Google Scholar 

  • Kim M, Hamilton SE, Guddat LW, Overall CM. Plant collagenase: unique collagenolytic activity of cysteine proteases from ginger. Biochimica et Biophysica Acta (BBA). 2007;1770:1627–35. https://doi.org/10.1016/j.bbagen.2007.08.003.

    Article 
    PubMed 

    Google Scholar 

  • Raskovic B, Bozovic O, Prodanovic R, Niketic V, Polovic N. Identification, purification and characterization of a novel collagenolytic serine protease from fig (Ficus carica var. Brown Turkey) latex. J Biosci Bioeng. 2014;118:622–7. https://doi.org/10.1016/j.jbiosc.2014.05.020.

    Article 
    PubMed 

    Google Scholar 

  • Peptidase M9A/M9B, collagenase, bacterial . [cited 2025 Jul 29]. https://www.ebi.ac.uk/interpro/entry/InterPro/IPR002169/. Accessed 29 Jul 2025

  • Q9X721 · COLG_HATHI [Internet]. [cited 2025 Jul 29]. https://www.uniprot.org/uniprotkb/Q9X721/entry. Accessed 29 Jul 2025

  • Collagenase [Internet]. [cited 2025 Jul 29]. https://www.ebi.ac.uk/interpro/entry/pfam/PF01752/. Accessed 29 Jul 2025

  • Rawlings ND, Barrett AJ, Bateman A. MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 2012;40:D343–50. https://doi.org/10.1093/nar/gkr987.

    Article 
    PubMed 

    Google Scholar 

  • Mookhtiar KA, Van Wart HE. Clostridium histolyticum collagenases: a new look at some old enzymes. Matrix. 1992;1(Suppl):116–26.

    PubMed 

    Google Scholar 

  • Hoy SM. Collagenase Clostridium histolyticum: a review in Peyronie’s disease. Clin Drug Investig. 2020;40:83–92. https://doi.org/10.1007/s40261-019-00867-5.

    Article 
    PubMed 

    Google Scholar 

  • Van Wart HE, Steinbrink DR. A continuous spectrophotometric assay for Clostridium histolyticum collagenase. Anal Biochem. 1981;113:356–65. https://doi.org/10.1016/0003-2697(81)90089-0.

    Article 
    PubMed 

    Google Scholar 

  • Matsushita O, Koide T, Kobayashi R, Nagata K, Okabe A. Substrate recognition by the collagen-binding domain of Clostridium histolyticum class I collagenase. J Biol Chem. 2001;276:8761–70. https://doi.org/10.1074/jbc.M003450200.

    Article 
    PubMed 

    Google Scholar 

  • Matsushita O, Jung C-M, Minami J, Katayama S, Nishi N, Okabe A. A study of the collagen-binding domain of a 116-kDa Clostridium histolyticum collagenase*. J Biol Chem. 1998;273(6):3643–8. https://doi.org/10.1074/jbc.273.6.3643.

    Article 
    PubMed 

    Google Scholar 

  • Matsushita O, Jung C-M, Katayama S, Minami J, Takahashi Y, Okabe A. Gene duplication and multiplicity of collagenases in Clostridium histolyticum. J Bacteriol. 1999;181:923–33. https://doi.org/10.1128/jb.181.3.923-933.1999.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • The R-B, Family C. The Collagen Family. Cold Spring Harb Perspect Biol. 2011;3:a004978–a004978. https://doi.org/10.1101/cshperspect.a004978.

    Article 

    Google Scholar 

  • Bella J, Hulmes DJS. Fibrillar Collagens. Fibrous Prot Struct Mech. 2017. https://doi.org/10.1007/978-3-319-49674-0_14.

    Article 

    Google Scholar 

  • Amirrah IN, Lokanathan Y, Zulkiflee I, Wee MFMR, Motta A, Fauzi MB. A comprehensive review on collagen type I development of biomaterials for tissue engineering: from biosynthesis to bioscaffold. Biomedicines. 2022;10:2307. https://doi.org/10.3390/biomedicines10092307.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Eckhard U, Schönauer E, Nüss D, Brandstetter H. Structure of collagenase G reveals a chew and digest mechanism of bacterial collagenolysis. Nat Struct Mol Biol. 2011;18:1109–14. https://doi.org/10.1038/nsmb.2127.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Eckhard U, Schönauer E, Brandstetter H. Structural basis for activity regulation and substrate preference of clostridial collagenases G, H, and T. J Biol Chem. 2013;288:20184–94. https://doi.org/10.1074/jbc.M112.448548.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Syed F, Thomas AN, Singh S, Kolluru V, Emeigh Hart SG, Bayat A. In vitro study of novel collagenase (XIAFLEX®) on Dupuytren’s disease fibroblasts displays unique drug related properties. PLoS One. 2012;7:e31430. https://doi.org/10.1371/journal.pone.0031430.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Watanabe-Nakayama T, Itami M, Kodera N, Ando T, Konno H. High-speed atomic force microscopy reveals strongly polarized movement of clostridial collagenase along collagen fibrils. Sci Rep. 2016;6:28975. https://doi.org/10.1038/srep28975.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mandl I. Bacterial collagenases and their clinical applications. Arzneimittelforschung. 1982;32:1381–4.

    PubMed 

    Google Scholar 

  • Ramundo J, Gray M. Collagenase for enzymatic debridement: a systematic review. J Wound Ostomy Continence Nurs. 2009;36:S4. https://doi.org/10.1097/WON.0b013e3181bfdf83.

    Article 
    PubMed 

    Google Scholar 

  • Drugs@FDA: FDA-Approved Drugs. [cited 2025 Jul 29]. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process. Accessed 29 Jul 2025

  • Waycaster C, Milne CT. Clinical and economic benefit of enzymatic debridement of pressure ulcers compared to autolytic debridement with a hydrogel dressing. J Med Econ. 2013;16:976–86. https://doi.org/10.3111/13696998.2013.807268.

    Article 
    PubMed 

    Google Scholar 

  • Ramundo J, Gray M. Enzymatic wound debridement. J Wound Ostomy Continence Nurs. 2008;35:273. https://doi.org/10.1097/01.WON.0000319125.21854.78.

    Article 
    PubMed 

    Google Scholar 

  • Kirshen C, Woo K, Ayello EA, Sibbald RG. Debridement: a vital component of wound bed preparation. Adv Skin Wound Care. 2006;19:518.

    Article 

    Google Scholar 

  • Karagol BS, Okumus N, Dursun A, Karadag N, Zencıroglu A. Early and successful enzymatic debridement via collagenase application to pinna in a preterm neonate. Pediatr Dermatol. 2011;28:600–1. https://doi.org/10.1111/j.1525-1470.2011.01546.x.

    Article 
    PubMed 

    Google Scholar 

  • Waycaster C, Carter MJ, Gilligan AM, Mearns ES, Fife CE, Milne CT. Comparative cost and clinical effectiveness of clostridial collagenase ointment for chronic dermal ulcers. J Comp Eff Res. 2018;7:149–65. https://doi.org/10.2217/cer-2017-0066.

    Article 
    PubMed 

    Google Scholar 

  • Abdel Raheem A, Johnson M, Ralph D, Garaffa G. Collagenase clostridium histolyticum: a novel medical treatment for Peyronie’s disease. Minerva Urol Nefrol. 2018. https://doi.org/10.23736/S0393-2249.18.03118-1.

    Article 
    PubMed 

    Google Scholar 

  • Furtado TP, Osadchiy V, Andino JJ, Eleswarapu SV, Mills JN. Collagenase Clostridium histolyticum for Peyronie’s disease: a contemporary atlas of complications and their management. Sex Med Rev. 2024;12:491–6. https://doi.org/10.1093/sxmrev/qeae004.

    Article 
    PubMed 

    Google Scholar 

  • FDA Approves Xiaflex for Debilitating Hand Condition. [cited 2025 Jul 29]. https://www.prnewswire.com/news-releases/fda-approves-xiaflex-for-debilitating-hand-condition-83391072.html. Accessed 29 Jul 2025

  • Hurst LC, Badalamente MA, Hentz VR, Hotchkiss RN, Kaplan FTD, Meals RA, et al. Injectable collagenase Clostridium histolyticum for Dupuytren’s contracture. N Engl J Med. 2009;361:968–79. https://doi.org/10.1056/NEJMoa0810866.

    Article 
    PubMed 

    Google Scholar 

  • Peimer CA, Wilbrand S, Gerber RA, Chapman D, Szczypa PP. Safety and tolerability of collagenase Clostridium histolyticum and fasciectomy for Dupuytren’s contracture. J Hand Surg Eur Vol. 2015;40:141–9. https://doi.org/10.1177/1753193414528843.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lunt SJ, Fyles A, Hill RP, Milosevic M. Interstitial fluid pressure in tumors: therapeutic barrier and biomarker of angiogenesis. Future Oncol. 2008;4:793–802. https://doi.org/10.2217/14796694.4.6.793.

    Article 
    PubMed 

    Google Scholar 

  • Cairns R, Papandreou I, Denko N. Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment. Mol Cancer Res. 2006;4:61–70. https://doi.org/10.1158/1541-7786.MCR-06-0002.

    Article 
    PubMed 

    Google Scholar 

  • Yata T, Lee ELQ, Suwan K, Syed N, Asavarut P, Hajitou A. Modulation of extracellular matrix in cancer is associated with enhanced tumor cell targeting by bacteriophage vectors. Mol Cancer. 2015;14:110. https://doi.org/10.1186/s12943-015-0383-4.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cemazar M, Golzio M, Sersa G, Escoffre J-M, Coer A, Vidic S, et al. Hyaluronidase and collagenase increase the transfection efficiency of gene electrotransfer in various murine tumors. Hum Gene Ther. 2012;23:128–37. https://doi.org/10.1089/hum.2011.073.

    Article 
    PubMed 

    Google Scholar 

  • Lo Cicero A, Campora S, Lo Buglio G, Cinà P, Lo Pinto M, Scilabra SD, et al. Enhancing therapeutic efficacy through degradation of endogenous extracellular matrix in primary breast tumor spheroids. FEBS J. 2025. https://doi.org/10.1111/febs.70069.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fan D, Cao Y, Cao M, Wang Y, Cao Y, Gong T. Nanomedicine in cancer therapy. Signal Transduct Target Ther. 2023;8:1–34. https://doi.org/10.1038/s41392-023-01536-y.

    Article 

    Google Scholar 

  • Fang J, Nakamura H, Maeda H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev. 2011;63:136–51. https://doi.org/10.1016/j.addr.2010.04.009.

    Article 
    PubMed 

    Google Scholar 

  • Maeda H. Macromolecular therapeutics in cancer treatment: the EPR effect and beyond. J Control Release. 2012;164:138–44. https://doi.org/10.1016/j.jconrel.2012.04.038.

    Article 
    PubMed 

    Google Scholar 

  • Wang Y, Zhou Q, Luo W, Yang X, Zhang J, Lou Y, et al. A collagenase-decorated Cu-based nanotheranostics: remodeling extracellular matrix for optimizing cuproptosis and MRI in pancreatic ductal adenocarcinoma. J Nanobiotechnol. 2024;22:689. https://doi.org/10.1186/s12951-024-02968-6.

    Article 

    Google Scholar 

  • Abdel-Hafez SM, Gallei M, Wagner S, Schneider M. Inhalable nano-structured microparticles for extracellular matrix modulation as a potential delivery system for lung cancer. Eur J Pharm Biopharm. 2024;204:114512. https://doi.org/10.1016/j.ejpb.2024.114512.

    Article 
    PubMed 

    Google Scholar 

  • Liu Q, Zou J, Chen Z, He W, Wu W. Current research trends of nanomedicines. Acta Pharm Sin B. 2023;13:4391–416. https://doi.org/10.1016/j.apsb.2023.05.018.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Koo H, Huh MS, Sun I-C, Yuk SH, Choi K, Kim K, et al. In vivo targeted delivery of nanoparticles for theranosis. Acc Chem Res. 2011;44:1018–28. https://doi.org/10.1021/ar2000138.

    Article 
    PubMed 

    Google Scholar 

  • Janib SM, Moses AS, MacKay JA. Imaging and drug delivery using theranostic nanoparticles. Adv Drug Deliv Rev. 2010;62:1052–63. https://doi.org/10.1016/j.addr.2010.08.004.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bae YH, Park K. Targeted drug delivery to tumors: myths, reality and possibility. J Control Release. 2011;153:198–205. https://doi.org/10.1016/j.jconrel.2011.06.001.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zinger A, Koren L, Adir O, Poley M, Alyan M, Yaari Z, et al. Collagenase nanoparticles enhance the penetration of drugs into pancreatic tumors. ACS Nano. 2019;13:11008–21. https://doi.org/10.1021/acsnano.9b02395.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu X, Dong X, Peng Z, Wang C, Wan J, Chen M, et al. Collagenase-functionalized liposomes based on enhancing penetration into the extracellular matrix augment therapeutic effect on idiopathic pulmonary fibrosis. AAPS PharmSciTech. 2025;26:113. https://doi.org/10.1208/s12249-025-03112-9.

    Article 
    PubMed 

    Google Scholar 

  • Zhou L, Liang Q, Li Y, Cao Y, Li J, Yang J, et al. Collagenase-I decorated co-delivery micelles potentiate extracellular matrix degradation and hepatic stellate cell targeting for liver fibrosis therapy. Acta Biomater. 2022;152:235–54. https://doi.org/10.1016/j.actbio.2022.08.065.

    Article 
    PubMed 

    Google Scholar 

  • Yu B, Wang W, Zhang Y, Sun Y, Li C, Liu Q, et al. Enhancing the tumor penetration of multiarm polymers by collagenase modification. Biomater Sci. 2024;12:2302–11. https://doi.org/10.1039/D3BM02123H.

    Article 
    PubMed 

    Google Scholar 

  • Xu F, Huang X, Wang Y, Zhou S. A size-changeable collagenase-modified nanoscavenger for increasing penetration and retention of nanomedicine in deep tumor tissue. Adv Mater. 2020;32:1906745. https://doi.org/10.1002/adma.201906745.

    Article 

    Google Scholar 

  • Wang J, Wu Q, Wang Y, Xiang L, Feng J, Zhou Z, et al. Collagenase-loaded pH-sensitive nanocarriers efficiently remodeled tumor stroma matrixes and improved the enrichment of nanomedicines. Nanoscale. 2021;13:9402–14. https://doi.org/10.1039/D1NR00950H.

    Article 
    PubMed 

    Google Scholar 

  • Liu Q, Wang L, Su Y, Dong W, Wang H, Liu Y, et al. Ultrahigh Enzyme Loading Metal-Organic Frameworks for Deep Tissue Pancreatic Cancer Photoimmunotherapy. Small. 2024;20:e2305131. https://doi.org/10.1002/smll.202305131.

    Article 
    PubMed 

    Google Scholar 

  • Abucafy MP, Galvao Frem RC, Polinario G, Pavan FR, Zhao H, Mielcarek A, et al. MIL-100(Fe) sub-micrometric capsules as a dual drug delivery system. Int J Mol Sci. 2022;23:7670. https://doi.org/10.3390/ijms23147670.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Oh JY, Seu M-S, Barui AK, Ok HW, Kim D, Choi E, et al. A multifunctional protein pre-coated metal–organic framework for targeted delivery with deep tissue penetration. Nanoscale. 2024;16:14748–56. https://doi.org/10.1039/D4NR02345E.

    Article 
    PubMed 

    Google Scholar 

  • Deng B, Huang R, Liang R, Fei Y, Luo Q, Song G. Design and evaluation of collagenase-loaded nanoparticles for mechanical intervention of orthotopic hepatocellular carcinoma in rat model. Int J Biol Macromol. 2025;285:138311. https://doi.org/10.1016/j.ijbiomac.2024.138311.

    Article 
    PubMed 

    Google Scholar 

  • Li J, Gong C, Chen X, Guo H, Tai Z, Ding N, et al. Biomimetic liposomal nanozymes improve breast cancer chemotherapy with enhanced penetration and alleviated hypoxia. J Nanobiotechnol. 2023;21(1):123. https://doi.org/10.1186/s12951-023-01874-7.

    Article 

    Google Scholar 

  • Luo J, Cao J, Ma G, Wang X, Sun Y, Zhang C, et al. Collagenase-loaded H-TiO2 nanoparticles enhance ultrasound imaging-guided sonodynamic therapy in a pancreatic carcinoma xenograft model via digesting stromal barriers. ACS Appl Mater Interfaces. 2022;14:40535–45. https://doi.org/10.1021/acsami.2c08951.

    Article 
    PubMed 

    Google Scholar 

  • Maksoudian C, Izci M, Salembier R, Gilabert IP, Gonçalves FR, Luci CR, et al. Gold nanoparticle delivery to solid tumors by macrophage depletion, hypoxia inhibition, and collagen degradation. ACS Appl Nano Mater. 2023;6:7605–18. https://doi.org/10.1021/acsanm.3c00780.

    Article 

    Google Scholar 

  • Murty S, Gilliland T, Qiao P, Tabtieng T, Higbee E, Al ZA, et al. Nanoparticles Functionalized with Collagenase Exhibit Improved Tumor Accumulation in a Murine Xenograft Model. Part Part Syst Charact. 2014;31:1307–12. https://doi.org/10.1002/ppsc.201400169.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang X-Y, Zhang J-G, Zhou Q-M, Yu J-N, Lu Y-F, Wang X-J, et al. Extracellular matrix modulating enzyme functionalized biomimetic Au nanoplatform-mediated enhanced tumor penetration and synergistic antitumor therapy for pancreatic cancer. J Nanobiotechnology. 2022;20:524. https://doi.org/10.1186/s12951-022-01738-6.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pan A, Zhaoyang W, Binlong C, Wenbing D, Hua Z, Bing H, et al. Localized co-delivery of collagenase and trastuzumab by thermosensitive hydrogels for enhanced antitumor efficacy in human breast xenograft. Drug Deliv. 2018;25:1495–503. https://doi.org/10.1080/10717544.2018.1474971.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Corder RD, Gadi SV, Vachieri RB, Jayes FL, Cullen JM, Khan SA, et al. Using rheology to quantify the effects of localized collagenase treatments on uterine fibroid digestion. Acta Biomater. 2021;134:443–52. https://doi.org/10.1016/j.actbio.2021.08.003.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen Y, Fan Z, Xu W, Zhu Z, Tan Z, Hu Y, et al. An injectable nanocomposite hydrogel with deep penetration ability for enhanced photothermal and chemotherapy. J Colloid Interface Sci. 2025;685:268–79. https://doi.org/10.1016/j.jcis.2025.01.146.

    Article 
    PubMed 

    Google Scholar 

  • Yang C, Liao X, Zhou K, Yao Y, He X, Zhong W, et al. Multifunctional nanoparticles and collagenase dual loaded thermosensitive hydrogel system for enhanced tumor-penetration, reversed immune suppression and photodynamic-immunotherapy. Bioact Mater. 2025;48:1–17. https://doi.org/10.1016/j.bioactmat.2025.02.014.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jansen CA, Cruijsen CWA, de Ruiter T, Nanlohy N, Willems N, Janssens-Korpela P, et al. Regulated expression of the inhibitory receptor LAIR-1 on human peripheral T cells during T cell activation and differentiation. Eur J Immunol. 2007;37:914–24. https://doi.org/10.1002/eji.200636678.

    Article 
    PubMed 

    Google Scholar 

  • Kohli AG, Kivimäe S, Tiffany MR, Szoka FC. Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan. J Control Release. 2014;191:105–14. https://doi.org/10.1016/j.jconrel.2014.05.019.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kohli AG, Kierstead PH, Venditto VJ, Walsh CL, Szoka FC. Designer lipids for drug delivery: from heads to tails. J Control Release. 2014;190:274–87. https://doi.org/10.1016/j.jconrel.2014.04.047.

    Article 
    PubMed 

    Google Scholar 

  • Rezvantalab S, Drude NI, Moraveji MK, Güvener N, Koons EK, Shi Y, et al. PLGA-based nanoparticles in cancer treatment. Front Pharmacol. 2018. https://doi.org/10.3389/fphar.2018.01260.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Narmani A, Jahedi R, Bakhshian-Dehkordi E, Ganji S, Nemati M, Ghahramani-Asl R, et al. Biomedical applications of PLGA nanoparticles in nanomedicine: advances in drug delivery systems and cancer therapy. Expert Opin Drug Deliv. 2023;20:937–54. https://doi.org/10.1080/17425247.2023.2223941.

    Article 
    PubMed 

    Google Scholar 

  • Kalyane D, Raval N, Maheshwari R, Tambe V, Kalia K, Tekade RK. Employment of enhanced permeability and retention effect (EPR): nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer. Mater Sci Eng C Mater Biol Appl. 2019;98:1252–76. https://doi.org/10.1016/j.msec.2019.01.066.

    Article 
    PubMed 

    Google Scholar 

  • Li B, Wen H-M, Cui Y, Zhou W, Qian G, Chen B. Emerging multifunctional metal-organic framework materials. Adv Mater. 2016;28:8819–60. https://doi.org/10.1002/adma.201601133.

    Article 
    PubMed 

    Google Scholar 

  • Bétard A, Fischer RA. Metal-organic framework thin films: from fundamentals to applications. Chem Rev. 2012;112:1055–83. https://doi.org/10.1021/cr200167v.

    Article 
    PubMed 

    Google Scholar 

  • Zhang Q, Kuang G, Li W, Wang J, Ren H, Zhao Y. Stimuli-responsive gene delivery nanocarriers for cancer therapy. Nano-Micro Lett. 2023;15:44. https://doi.org/10.1007/s40820-023-01018-4.

    Article 

    Google Scholar 

  • Li Y, Dong H, Wang K, Shi D, Zhang X, Zhuo R. Stimulus-responsive polymeric nanoparticles for biomedical applications. Sci China Chem. 2010;53:447–57. https://doi.org/10.1007/s11426-010-0101-4.

    Article 

    Google Scholar 

  • Mi P. Stimuli-responsive nanocarriers for drug delivery, tumor imaging, therapy and theranostics. Theranostics. 2020;10:4557–88. https://doi.org/10.7150/thno.38069.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hajebi S, Rabiee N, Bagherzadeh M, Ahmadi S, Rabiee M, Roghani-Mamaqani H, et al. Stimulus-responsive polymeric nanogels as smart drug delivery systems. Acta Biomater. 2019;92:1–18. https://doi.org/10.1016/j.actbio.2019.05.018.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wei D, Sun Y, Zhu H, Fu Q. Stimuli-responsive polymer-based nanosystems for cancer theranostics. ACS Nano. 2023;17:23223–61. https://doi.org/10.1021/acsnano.3c06019.

    Article 
    PubMed 

    Google Scholar 

  • Zou M, Shen C, Peng W, Zhang L, Liu W, Lv Y. A biomimetic nanoplatform with mechano-metabolic microenvironment and hypoxic microenvironment programming ability for enhanced chemo-immunotherapy. Chem Eng J. 2025;513:163088. https://doi.org/10.1016/j.cej.2025.163088.

    Article 

    Google Scholar 

  • Kuhn SJ, Finch SK, Hallahan DE, Giorgio TD. Proteolytic surface functionalization enhances in vitro magnetic nanoparticle mobility through extracellular matrix. Nano Lett. 2006;6:306–12. https://doi.org/10.1021/nl052241g.

    Article 
    PubMed 

    Google Scholar 

  • Mauro N, Scialabba C, Puleio R, Varvara P, Licciardi M, Cavalaro G, et al. SPIONs embedded in polyamino acid nanogels to synergistically treat tumor microenvironment and breast cancer cells. Int J Pharm. 2019;555:207–19. https://doi.org/10.1016/j.ijpharm.2018.11.046.

    Article 
    PubMed 

    Google Scholar 

  • Yin T, Chen H, Ma A, Pan H, Chen Z, Tang X, et al. Cleavable collagenase-assistant nanosonosensitizer for tumor penetration and sonodynamic therapy. Biomaterials. 2023;293:121992. https://doi.org/10.1016/j.biomaterials.2022.121992.

    Article 
    PubMed 

    Google Scholar 

  • Sun R, Zhang Y, Piao Y, Xiang J, Shao S, Zhou Q, et al. Dual enzyme-responsive polymer-drug conjugates induce diverse cells mutual transcytosis to achieve deep pancreatic tumor penetration. Angew Chem Int Ed Engl. 2025. https://doi.org/10.1002/anie.202506038.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • LeBeau AM, Brennen WN, Aggarwal S, Denmeade SR. Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin. Mol Cancer Ther. 2009;8:1378–86. https://doi.org/10.1158/1535-7163.MCT-08-1170.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Brennen WN, Rosen DM, Wang H, Isaacs JT, Denmeade SR. Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. JNCI J Natl Cancer Inst. 2012;104:1320–34. https://doi.org/10.1093/jnci/djs336.

    Article 
    PubMed 

    Google Scholar 

  • Zana A, Galbiati A, Gilardoni E, Bocci M, Millul J, Sturm T, et al. Fibroblast activation protein triggers release of drug payload from non-internalizing small molecule drug conjugates in solid tumors. Clin Cancer Res. 2022;28:5440–54. https://doi.org/10.1158/1078-0432.CCR-22-1788.

    Article 
    PubMed 

    Google Scholar 

  • Li Z, Mo F, Guo K, Ren S, Wang Y, Chen Y, et al. Nanodrug-bacteria conjugates-mediated oncogenic collagen depletion enhances immune checkpoint blockade therapy against pancreatic cancer. Med. 2024;5:348-367.e7. https://doi.org/10.1016/j.medj.2024.02.012.

    Article 
    PubMed 

    Google Scholar 

  • Qi L, Duan B-W, Wang H, Liu Y-J, Han H, Han M-M, et al. Reactive oxygen species-responsive nanoparticles toward extracellular matrix normalization for pancreatic fibrosis regression. Adv Sci. 2024;11:2401254. https://doi.org/10.1002/advs.202401254.

    Article 

    Google Scholar 

  • Zhou D, Duan Z, Li Z, Ge F, Wei R, Kong L. The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment. Front Pharmacol. 2022. https://doi.org/10.3389/fphar.2022.1091779.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Abaza M, Luqmani YA. The influence of pH and hypoxia on tumor metastasis. Expert Rev Anticancer Ther. 2013;13:1229–42. https://doi.org/10.1586/14737140.2013.843455.

    Article 
    PubMed 

    Google Scholar 

  • Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15:325–40. https://doi.org/10.1038/nrclinonc.2018.29.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26(5):605–22. https://doi.org/10.1016/j.ccell.2014.10.006.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang X, Lin Y, Gillies RJ. Tumor pH and its measurement. J Nucl Med. 2010;51:1167–70. https://doi.org/10.2967/jnumed.109.068981.

    Article 
    PubMed 

    Google Scholar 

  • Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer. 2014;14:430–9. https://doi.org/10.1038/nrc3726.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ji F, Wang Y, Qiu L, Li S, Zhu J, Liang Z, et al. Hypoxia inducible factor 1α-mediated LOX expression correlates with migration and invasion in epithelial ovarian cancer. Int J Oncol. 2013;42:1578–88. https://doi.org/10.3892/ijo.2013.1878.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Januzzi JL, Garasic JM, Kasner SE, McDonald V, Petrie MC, Seltzer J, et al. Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee. J Hematol Oncol. 2022;15:1. https://doi.org/10.1186/s13045-021-01221-z.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fais S, Venturi G, Gatenby B. Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy. Cancer Metastasis Rev. 2014;33:1095–108. https://doi.org/10.1007/s10555-014-9531-3.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lee S-H, McIntyre D, Honess D, Hulikova A, Pacheco-Torres J, Cerdán S, et al. Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo. Br J Cancer. 2018;119:622–30. https://doi.org/10.1038/s41416-018-0216-5.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Büscheck F, Fraune C, Simon R, Kluth M, Hube-Magg C, Möller-Koop C, et al. Aberrant expression of membranous carbonic anhydrase IX (CAIX) is associated with unfavorable disease course in papillary and clear cell renal cell carcinoma. Urol Oncol Semin Orig Investig. 2018;36:531.e19-531.e25. https://doi.org/10.1016/j.urolonc.2018.08.015.

    Article 

    Google Scholar 

  • Panisova E, Kery M, Sedlakova O, Brisson L, Debreova M, Sboarina M, et al. Lactate stimulates CA IX expression in normoxic cancer cells. Oncotarget. 2017;8:77819–35. https://doi.org/10.18632/oncotarget.20836.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Vaupel P, Multhoff G. Fatal Alliance of Hypoxia-/HIF-1α-Driven Microenvironmental Traits Promoting Cancer Progression. Oxyg Transp Tissue XLI. 2020. https://doi.org/10.1007/978-3-030-34461-0_21.

    Article 

    Google Scholar 

  • Gonzalez-Avila G, Sommer B, Flores-Soto E, Aquino-Galvez A. Hypoxic effects on matrix metalloproteinases’ expression in the tumor microenvironment and therapeutic perspectives. Int J Mol Sci. 2023;24:16887. https://doi.org/10.3390/ijms242316887.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Springer M, Burakgazi ZA, Domukhovska A, Nafchi B, Beary MC, Acquisto A, et al. HIF-1α-mediated disruption of cellular junctions: the impact of hypoxia on the tumor microenvironment and invasion. Int J Mol Sci. 2025;26:5101. https://doi.org/10.3390/ijms26115101.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang Y, Zhai Z, Duan J, Wang X, Zhong J, Wu L, et al. Lactate: the mediator of metabolism and immunosuppression. Front Endocrinol (Lausanne). 2022. https://doi.org/10.3389/fendo.2022.901495.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhou Y, Lou J, Tian Y, Ding J, Wang X, Tang B. How lactate affects immune strategies in lymphoma. Front Mol Biosci. 2024. https://doi.org/10.3389/fmolb.2024.1480884.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rahman MA, Yadab MK, Ali MM. Emerging role of extracellular pH in tumor microenvironment as a therapeutic target for cancer immunotherapy. Cells. 2024;13:1924. https://doi.org/10.3390/cells13221924.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Saadat M, Mostafaei F, Mahdinloo S, Abdi M, Zahednezhad F, Zakeri-Milani P, et al. Drug delivery of pH-sensitive nanoparticles into the liver cancer cells. J Drug Deliv Sci Technol. 2021;63:102557. https://doi.org/10.1016/j.jddst.2021.102557.

    Article 

    Google Scholar 

  • Lim E-K, Chung BH, Chung SJ. Recent advances in pH-sensitive polymeric nanoparticles for smart drug delivery in cancer therapy. Curr Drug Targets. 2018;19:300–17. https://doi.org/10.2174/1389450117666160602202339.

    Article 
    PubMed 

    Google Scholar 

  • Zhang J, Zheng Y, Xie X, Wang L, Su Z, Wang Y, et al. Cleavable multifunctional targeting mixed micelles with sequential pH-triggered TAT peptide activation for improved antihepatocellular carcinoma efficacy. Mol Pharm. 2017;14:3644–59. https://doi.org/10.1021/acs.molpharmaceut.7b00404.

    Article 
    PubMed 

    Google Scholar 

  • Zhang C, An T, Wang D, Wan G, Zhang M, Wang H, et al. Stepwise pH-responsive nanoparticles containing charge-reversible pullulan-based shells and poly(β-amino ester)/poly(lactic-co-glycolic acid) cores as carriers of anticancer drugs for combination therapy on hepatocellular carcinoma. J Control Release. 2016;226:193–204. https://doi.org/10.1016/j.jconrel.2016.02.030.

    Article 
    PubMed 

    Google Scholar 

  • Zheng S, Wang J, Ding N, Chen W, Chen H, Xue M, et al. Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer. J Nanobiotechnol. 2021;19:381. https://doi.org/10.1186/s12951-021-01127-5.

    Article 

    Google Scholar 

  • Mesoporous silica nanoparticles. facile surface functionalization and versatile biomedical applications in oncology. Acta Biomater. 2020;116:1–15. https://doi.org/10.1016/j.actbio.2020.09.009.

    Article 

    Google Scholar 

  • Narayan R, Nayak UY, Raichur AM, Garg S. Mesoporous silica nanoparticles: a comprehensive review on synthesis and recent advances. Pharmaceutics. 2018;10:118. https://doi.org/10.3390/pharmaceutics10030118.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gu J, Su S, Zhu M, Li Y, Zhao W, Duan Y, et al. Targeted doxorubicin delivery to liver cancer cells by PEGylated mesoporous silica nanoparticles with a pH-dependent release profile. Microporous Mesoporous Mater. 2012;161:160–7. https://doi.org/10.1016/j.micromeso.2012.05.035.

    Article 

    Google Scholar 

  • Li M, Zhao G, Su W-K, Shuai Q. Enzyme-responsive nanoparticles for anti-tumor drug delivery. Front Chem. 2020. https://doi.org/10.3389/fchem.2020.00647.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Shahriari M, Zahiri M, Abnous K, Taghdisi SM, Ramezani M, Alibolandi M. Enzyme responsive drug delivery systems in cancer treatment. J Control Release. 2019;308:172–89. https://doi.org/10.1016/j.jconrel.2019.07.004.

    Article 
    PubMed 

    Google Scholar 

  • Kuang T, Liu Y, Gong T, Peng X, Hu X, Yu Z. Enzyme-responsive nanoparticles for anticancer drug delivery. Curr Nanosci. 2015;12:38–46. https://doi.org/10.2174/1573413711666150624170518.

    Article 

    Google Scholar 

  • Zhao X, Wang T, Liu W, Wang C, Wang D, Shang T, et al. Multifunctional Au@IPN-pNIPAAm nanogels for cancer cell imaging and combined chemo-photothermal treatment. J Mater Chem. 2011;21:7240–7. https://doi.org/10.1039/C1JM10277J.

    Article 

    Google Scholar 

  • Shang T, Wang C, Ren L, Tian X, Li D, Ke X, et al. Synthesis and characterization of NIR-responsive Aurod@pNIPAAm-PEGMA nanogels as vehicles for delivery of photodynamic therapy agents. Nanoscale Res Lett. 2013;8:4. https://doi.org/10.1186/1556-276X-8-4.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Heskins M, Guillet JE. Solution properties of poly(N-isopropylacrylamide). Journal of Macromolecular Science: Part A. 1968;2:1441–55. https://doi.org/10.1080/10601326808051910.

    Article 

    Google Scholar 

  • Tauer K, Gau D, Schulze S, Völkel A, Dimova R. Thermal property changes of poly(N-isopropylacrylamide) microgel particles and block copolymers. Colloid Polym Sci. 2009;287:299–312. https://doi.org/10.1007/s00396-008-1984-x.

    Article 

    Google Scholar 

  • Van Durme K, Van Assche G, Van Mele B. Kinetics of demixing and remixing in poly(N-isopropylacrylamide)/water studied by modulated temperature DSC. Macromolecules. 2004;37:9596–605. https://doi.org/10.1021/ma048472b.

    Article 

    Google Scholar 

  • Sung B, Kim C, Kim M-H. Biodegradable colloidal microgels with tunable thermosensitive volume phase transitions for controllable drug delivery. J Colloid Interface Sci. 2015;450:26–33. https://doi.org/10.1016/j.jcis.2015.02.068.

    Article 
    PubMed 

    Google Scholar 

  • Materón EM, Miyazaki CM, Carr O, Joshi N, Picciani PHS, Dalmaschio CJ, et al. Magnetic nanoparticles in biomedical applications: a review. Applied Surface Science Advances. 2021;6:100163. https://doi.org/10.1016/j.apsadv.2021.100163.

    Article 

    Google Scholar 

  • Rezaei B, Yari P, Sanders SM, Wang H, Chugh VK, Liang S, et al. Magnetic Nanoparticles: A Review on Synthesis, Characterization, Functionalization, and Biomedical Applications. Small. 2024;20:e2304848. https://doi.org/10.1002/smll.202304848.

    Article 
    PubMed 

    Google Scholar 

  • Zewail MB, Yang G, Fan Y, Hui Y, Zhao C-X, Liu Y. Cell membrane-coated lipid nanoparticles for drug delivery. Aggregate. 2025. https://doi.org/10.1002/agt2.70054.

    Article 

    Google Scholar 

  • Alimohammadvand S, Kaveh Zenjanab M, Mashinchian M, Shayegh J, Jahanban-Esfahlan R. Recent advances in biomimetic cell membrane–camouflaged nanoparticles for cancer therapy. Biomed Pharmacother. 2024;177:116951. https://doi.org/10.1016/j.biopha.2024.116951.

    Article 
    PubMed 

    Google Scholar 

  • Zhang Y, Zhang Q, Li C, Zhou Z, Lei H, Liu M, et al. Advances in cell membrane-based biomimetic nanodelivery systems for natural products. Drug Deliv. 2024;31:2361169. https://doi.org/10.1080/10717544.2024.2361169.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li B, Fei W, Lijuan G, Qing H, Yuxin Y, Chen H. The Potential of Biomimetic Nanoparticles for Tumor-Targeted Drug Delivery. Nanomedicine. 2018;13:2099–118. https://doi.org/10.2217/nnm-2018-0017.

    Article 
    PubMed 

    Google Scholar 

  • Tan A, Rajadas J, Seifalian AM. Exosomes as nano-theranostic delivery platforms for gene therapy. Adv Drug Deliv Rev. 2013;65:357–67. https://doi.org/10.1016/j.addr.2012.06.014.

    Article 
    PubMed 

    Google Scholar 

  • Sun D, Zhuang X, Zhang S, Deng Z-B, Grizzle W, Miller D, et al. Exosomes are endogenous nanoparticles that can deliver biological information between cells. Adv Drug Deliv Rev. 2013;65:342–7. https://doi.org/10.1016/j.addr.2012.07.002.

    Article 
    PubMed 

    Google Scholar 

  • Shi Y, Zhang J, Li Y, Feng C, Shao C, Shi Y, et al. Engineered mesenchymal stem/stromal cells against cancer. Cell Death Dis. 2025;16:113. https://doi.org/10.1038/s41419-025-07443-0.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Minev T, Balbuena S, Gill JM, Marincola FM, Kesari S, Lin F. Mesenchymal stem cells – the secret agents of cancer immunotherapy: promises, challenges, and surprising twists. Oncotarget. 2024;15:793–805. https://doi.org/10.18632/oncotarget.28672.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pegtel DM, Gould SJ. Exosomes. Annu Rev Biochem. 2019;88:487–514. https://doi.org/10.1146/annurev-biochem-013118-111902.

    Article 
    PubMed 

    Google Scholar 

  • Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics. 2010;73:1907–20. https://doi.org/10.1016/j.jprot.2010.06.006.

    Article 
    PubMed 

    Google Scholar 

  • Freitas C, Sousa C, Machado F, Serino M, Santos V, Cruz-Martins N, et al. The role of liquid biopsy in early diagnosis of lung cancer. Front Oncol. 2021. https://doi.org/10.3389/fonc.2021.634316.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Baig MS, Roy A, Rajpoot S, Liu D, Savai R, Banerjee S, et al. Tumor-derived exosomes in the regulation of macrophage polarization. Inflamm Res. 2020;69:435–51. https://doi.org/10.1007/s00011-020-01318-0.

    Article 
    PubMed 

    Google Scholar 

  • Long L, Zhang X, Bai J, Li Y, Wang X, Zhou Y.

    Tissue-specific and exosomal miRNAs in lung cancer radiotherapy: from regulatory mechanisms to clinical implications

    . Cancer Manag Res. 2019;11:4413–24. https://doi.org/10.2147/CMAR.S198966.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hakulinen J, Sankkila L, Sugiyama N, Lehti K, Keski-Oja J. Secretion of active membrane type 1 matrix metalloproteinase (MMP-14) into extracellular space in microvesicular exosomes. J Cell Biochem. 2008;105:1211–8. https://doi.org/10.1002/jcb.21923.

    Article 
    PubMed 

    Google Scholar 

  • Sanderson RD, Bandari SK, Vlodavsky I. Proteases and glycosidases on the surface of exosomes: newly discovered mechanisms for extracellular remodeling. Matrix Biol. 2019;75:160–9. https://doi.org/10.1016/j.matbio.2017.10.007.

    Article 
    PubMed 

    Google Scholar 

  • Li T, Yan Y, Wang B, Qian H, Zhang X, Shen L, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 2013;22:845–54. https://doi.org/10.1089/scd.2012.0395.

    Article 
    PubMed 

    Google Scholar 

  • Zhao B, Shi X, Feng D, Han J, Hu D. MicroRNA let-7d attenuates hypertrophic scar fibrosis through modulation of iron metabolism by reducing DMT1 expression. J Mol Histol. 2023;54:77–87. https://doi.org/10.1007/s10735-023-10113-0.

    Article 
    PubMed 

    Google Scholar 

  • Yin F, Wang W-Y, Mao L-C, Cai Q-Q, Jiang W-H. Effect of human umbilical cord mesenchymal stem cells transfected with HGF on TGF-β1/Smad signaling pathway in carbon tetrachloride-induced liver fibrosis rats. Stem Cells Dev. 2020;29:1395–406. https://doi.org/10.1089/scd.2020.0060.

    Article 
    PubMed 

    Google Scholar 

  • Yang J, Hu H, Zhang S, Jiang L, Cheng Y, Xie H, et al. Human umbilical cord mesenchymal stem cell-derived exosomes alleviate pulmonary fibrosis in mice by inhibiting epithelial-mesenchymal transition. Nan Fang Yi Ke Da Xue Xue Bao. 2020;40:988–94. https://doi.org/10.2122/j.issn.1673-4254.2020.07.11.

    Article 
    PubMed 

    Google Scholar 

  • Baglio SR, Pegtel DM, Baldini N. Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol. 2012;3:359. https://doi.org/10.3389/fphys.2012.00359.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lou G, Chen Z, Zheng M, Liu Y. Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp Mol Med. 2017;49:e346. https://doi.org/10.1038/emm.2017.63.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li J, Ghazwani M, Zhang Y, Lu J, Li J, Fan J, et al. MiR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression. J Hepatol. 2013;58:522–8. https://doi.org/10.1016/j.jhep.2012.11.011.

    Article 
    PubMed 

    Google Scholar 

  • Milosavljevic N, Gazdic M, Simovic Markovic B, Arsenijevic A, Nurkovic J, Dolicanin Z, et al. Mesenchymal stem cells attenuate liver fibrosis by suppressing Th17 cells – an experimental study. Transplant Int. 2018;31(1):102–15. https://doi.org/10.1111/tri.13023.

    Article 

    Google Scholar 

  • Dooley S, ten Dijke P. TGF-β in progression of liver disease. Cell Tissue Res. 2012;347:245–56. https://doi.org/10.1007/s00441-011-1246-y.

    Article 
    PubMed 

    Google Scholar 

  • Brenner DA. Transforming growth factor B and hepatic fibrosis: cause or effect? Hepatology. 1991;14:740–2.

    PubMed 

    Google Scholar 

  • Arias M, Lahme B, Van de Leur E, Gressner AM, Weiskirchen R. Adenoviral delivery of an antisense RNA complementary to the 3’ coding sequence of transforming growth factor-beta1 inhibits fibrogenic activities of hepatic stellate cells. Cell Growth Differ. 2002;13:265–73.

    PubMed 

    Google Scholar 

  • Liu X, Wang H, Yang M, Hou Y, Chen Y, Bie P. Exosomal miR-29b from cancer-associated fibroblasts inhibits the migration and invasion of hepatocellular carcinoma cells. Transl Cancer Res. 2020. https://doi.org/10.21037/tcr.2020.02.68.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fang J-H, Zhou H-C, Zeng C, Yang J, Liu Y, Huang X, et al. Microrna-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology. 2011;54:1729–40. https://doi.org/10.1002/hep.24577.

    Article 
    PubMed 

    Google Scholar 

  • Forbes SJ, Gupta S, Dhawan A. Cell therapy for liver disease: From liver transplantation to cell factory. J Hepatol. 2015;62:S157–69. https://doi.org/10.1016/j.jhep.2015.02.040.

    Article 
    PubMed 

    Google Scholar 

  • Trombino S, Servidio C, Curcio F, Cassano R. Strategies for hyaluronic acid-based hydrogel design in drug delivery. Pharmaceutics. 2019;11:407. https://doi.org/10.3390/pharmaceutics11080407.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fan S, Liu Q, Dong J, Ai X, Li J, Huang W, et al. In situ forming an injectable hyaluronic acid hydrogel for drug delivery and synergistic tumor therapy. Heliyon. 2024;10:e32135. https://doi.org/10.1016/j.heliyon.2024.e32135.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kim JH, Moon MJ, Kim DY, Heo SH, Jeong YY. Hyaluronic acid-based nanomaterials for cancer therapy. Polymers. 2018;10:1133. https://doi.org/10.3390/polym10101133.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Qin Y, Geng X, Sun Y, Zhao Y, Chai W, Wang X, et al. Ultrasound nanotheranostics: toward precision medicine. J Control Release. 2023;353:105–24. https://doi.org/10.1016/j.jconrel.2022.11.021.

    Article 
    PubMed 

    Google Scholar 

  • Son S, Kim JH, Wang X, Zhang C, Yoon SA, Shin J, et al. Multifunctional sonosensitizers in sonodynamic cancer therapy. Chem Soc Rev. 2020;49:3244–61. https://doi.org/10.1039/C9CS00648F.

    Article 
    PubMed 

    Google Scholar 

  • Zhang Y, Zhang X, Yang H, Yu L, Xu Y, Sharma A, et al. Advanced biotechnology-assisted precise sonodynamic therapy. Chem Soc Rev. 2021;50:11227–48. https://doi.org/10.1039/D1CS00403D.

    Article 
    PubMed 

    Google Scholar 

  • Continuous inertial cavitation evokes massive ROS for reinforcing sonodynamic therapy and immunogenic cell death against breast carcinoma. Nano Today. 2021;36:101009. https://doi.org/10.1016/j.nantod.2020.101009

  • Wang H, Guo J, Lin W, Fu Z, Ji X, Yu B, et al. Open-shell nanosensitizers for glutathione responsive cancer sonodynamic therapy. Adv Mater. 2022;34:2110283. https://doi.org/10.1002/adma.202110283.

    Article 

    Google Scholar 

  • Zheng X, Goins BA, Cameron IL, Santoyo C, Bao A, Frohlich VC, et al. Ultrasound-guided intratumoral administration of collagenase-2 improved liposome drug accumulation in solid tumor xenografts. Cancer Chemother Pharmacol. 2011;67:173–82. https://doi.org/10.1007/s00280-010-1305-1.

    Article 
    PubMed 

    Google Scholar 

  • Brennen WN, Isaacs JT, Denmeade SR. Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther. 2012;11:257–66. https://doi.org/10.1158/1535-7163.MCT-11-0340.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Koczorowska Mm, Tholen S, Bucher F, Lutz L, Kizhakkedathu Jn, De Wever O, et al. Fibroblast activation protein-α, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations. Mol Oncol. 2016;10:40–58. https://doi.org/10.1016/j.molonc.2015.08.001.

    Article 
    PubMed 

    Google Scholar 

  • Nissen NI, Karsdal M, Willumsen N. Collagens and cancer associated fibroblasts in the reactive stroma and its relation to cancer biology. J Exp Clin Cancer Res. 2019;38:115. https://doi.org/10.1186/s13046-019-1110-6.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Levy MT, McCaughan GW, Abbott CA, Park JE, Cunningham AM, Müller E, et al. Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis. Hepatology. 1999;29:1768–78. https://doi.org/10.1002/hep.510290631.

    Article 
    PubMed 

    Google Scholar 

  • Meng S, Hara T, Miura Y, Ishii H. Fibroblast activation protein constitutes a novel target of chimeric antigen receptor T-cell therapy in solid tumors. Cancer Sci. 2024;115:3532–42. https://doi.org/10.1111/cas.16285.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Garin-Chesa P, Old LJ, Rettig WJ. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci U S A. 1990;87:7235–9. https://doi.org/10.1073/pnas.87.18.7235.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rettig WJ, Garin-Chesa P, Healey JH, Su SL, Ozer HL, Schwab M, et al. Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. Cancer Res. 1993;53:3327–35. http://www.ncbi.nlm.nih.gov/pubmed/8391923

  • Brennen WN, Thorek JDL, Jiang W, Krueger TE, Antony L, Denmeade SR, et al. Overcoming stromal barriers to immuno-oncological responses via fibroblast activation protein-targeted therapy. Immunotherapy. 2021;13:155–75. https://doi.org/10.2217/imt-2020-0066.

    Article 
    PubMed 

    Google Scholar 

  • Fang J, Xiao L, Joo K-I, Liu Y, Zhang C, Liu S, et al. A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice. Int J Cancer. 2016;138:1013–23. https://doi.org/10.1002/ijc.29831.

    Article 
    PubMed 

    Google Scholar 

  • Fang J, Hu B, Li S, Zhang C, Liu Y, Wang P. A multi-antigen vaccine in combination with an immunotoxin targeting tumor-associated fibroblast for treating murine melanoma. Mol Ther. 2016;3:16007. https://doi.org/10.1038/mto.2016.7.

    Article 

    Google Scholar 

  • Xia Q, Zhang F-F, Geng F, Liu C-L, Xu P, Lu Z-Z, et al. Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model. Cancer Immunol Immunother. 2016;65:613–24. https://doi.org/10.1007/s00262-016-1827-4.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Duperret EK, Trautz A, Ammons D, Perales-Puchalt A, Wise MC, Yan J, et al. Alteration of the tumor stroma using a consensus DNA vaccine targeting fibroblast activation protein (FAP) synergizes with antitumor vaccine therapy in mice. Clin Cancer Res. 2018;24:1190–201. https://doi.org/10.1158/1078-0432.CCR-17-2033.

    Article 
    PubMed 

    Google Scholar 

  • Teng C, Zhang B, Yuan Z, Kuang Z, Chai Z, Ren L, et al. Fibroblast activation protein-α-adaptive micelles deliver anti-cancer drugs and reprogram stroma fibrosis. Nanoscale. 2020;12:23756–67. https://doi.org/10.1039/d0nr04465b.

    Article 
    PubMed 

    Google Scholar 

  • Zhang Y, Zhou J, Chen X, Li Z, Gu L, Pan D, et al. Modulating tumor-stromal crosstalk via a redox-responsive nanomedicine for combination tumor therapy. J Control Release. 2023;356:525–41. https://doi.org/10.1016/j.jconrel.2023.03.015.

    Article 
    PubMed 

    Google Scholar 

  • Zhou S, Zhen Z, Paschall AV, Xue L, Yang X, Bebin Blackwell A-G, et al. FAP-targeted photodynamic therapy mediated by ferritin nanoparticles elicits an immune response against cancer cells and cancer associated fibroblasts. Adv Funct Mater. 2021;31:2007017. https://doi.org/10.1002/adfm.202007017.

    Article 
    PubMed 

    Google Scholar 

  • Gao C, Jian C, Wang L, Liu Y, Xiong Y, Wu T, et al. FAP-targeting biomimetic nanosystem to restore the activated cancer-associated fibroblasts to quiescent state for breast cancer radiotherapy. Int J Pharm. 2025;670:125190. https://doi.org/10.1016/j.ijpharm.2025.125190.

    Article 
    PubMed 

    Google Scholar 

  • Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20:359–71. https://doi.org/10.1038/s41571-023-00754-1.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rao S, Kiick KL. Recent advances in extracellular matrix-inspired nanocarriers. Expert Opin Drug Deliv. 2025. https://doi.org/10.1080/17425247.2025.2519809.

    Article 
    PubMed 

    Google Scholar 

  • Peng L, Sferruzza G, Yang L, Zhou L, Chen S. CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors. Cell Mol Immunol. 2024;21(10):1089–108. https://doi.org/10.1038/s41423-024-01207-0.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Schuberth PC, Hagedorn C, Jensen SM, Gulati P, van den Broek M, Mischo A, et al. Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells. J Transl Med. 2013;11:187. https://doi.org/10.1186/1479-5876-11-187.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang L-CS, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res. 2014;2:154–66. https://doi.org/10.1158/2326-6066.CIR-13-0027.

    Article 
    PubMed 

    Google Scholar 

  • Rodriguez-Garcia A, Palazon A, Noguera-Ortega E, Powell DJ, Guedan S. Car-T cells hit the tumor microenvironment: strategies to overcome tumor escape. Front Immunol. 2020;11:1109. https://doi.org/10.3389/fimmu.2020.01109.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Roberts EW, Deonarine A, Jones JO, Denton AE, Feig C, Lyons SK, et al. Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia. J Exp Med. 2013;210:1137–51. https://doi.org/10.1084/jem.20122344.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tran E, Chinnasamy D, Yu Z, Morgan RA, Lee C-CR, Restifo NP, et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med. 2013;210:1125–35. https://doi.org/10.1084/jem.20130110.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Loeffler M, Krüger JA, Niethammer AG, Reisfeld RA. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Investig. 2006;116:1955–62. https://doi.org/10.1172/JCI26532.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lee J, Fassnacht M, Nair S, Boczkowski D, Gilboa E. Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts. Cancer Res. 2005;65:11156–63. https://doi.org/10.1158/0008-5472.CAN-05-2805.

    Article 
    PubMed 

    Google Scholar 

  • Wen Y, Wang C-T, Ma T-T, Li Z-Y, Zhou L-N, Mu B, et al. Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci. 2010;101:2325–32. https://doi.org/10.1111/j.1349-7006.2010.01695.x.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kakarla S, Chow KKH, Mata M, Shaffer DR, Song X-T, Wu M-F, et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol Ther. 2013;21:1611–20. https://doi.org/10.1038/mt.2013.110.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wang W, Hu K, Xue J, Chen J, Du X, Zhao T, et al. In vivo FAP-CAR macrophages enhance chemotherapy and immunotherapy against pancreatic cancer by removing the fibrosis barrier. J Control Release. 2025;384:113888. https://doi.org/10.1016/j.jconrel.2025.113888.

    Article 
    PubMed 

    Google Scholar 

  • Ruixin S, Yifan L, Yansha S, Min Z, Yiwei D, Xiaoli H, et al. Dual targeting chimeric antigen receptor cells enhance antitumour activity by overcoming T cell exhaustion in pancreatic cancer. Br J Pharmacol. 2024;181:4628–46. https://doi.org/10.1111/bph.16505.

    Article 
    PubMed 

    Google Scholar 

  • Augsten M. Cancer-Associated Fibroblasts as Another Polarized Cell Type of the Tumor Microenvironment. Front Oncol. 2014. https://doi.org/10.3389/fonc.2014.00062.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yoshida GJ. Regulation of heterogeneous cancer-associated fibroblasts: the molecular pathology of activated signaling pathways. J Exp Clin Cancer Res. 2020;39:112. https://doi.org/10.1186/s13046-020-01611-0.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chen C-Y, Yang S-H, Chang P-Y, Chen S-F, Nieh S, Huang W-Y, et al. Cancer-associated-fibroblast-mediated paracrine and autocrine SDF-1/CXCR4 signaling promotes stemness and aggressiveness of colorectal cancers. Cells. 2024;13:1334. https://doi.org/10.3390/cells13161334.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tan H-X, Gong W-Z, Zhou K, Xiao Z-G, Hou F-T, Huang T, et al. CXCR4/TGF-β1 mediated hepatic stellate cells differentiation into carcinoma-associated fibroblasts and promoted liver metastasis of colon cancer. Cancer Biol Ther. 2020;21:258–68. https://doi.org/10.1080/15384047.2019.1685157.

    Article 
    PubMed 

    Google Scholar 

  • Sugihara H, Ishimoto T, Yasuda T, Izumi D, Eto K, Sawayama H, et al. Cancer-associated fibroblast-derived CXCL12 causes tumor progression in adenocarcinoma of the esophagogastric junction. Med Oncol. 2015;32:168. https://doi.org/10.1007/s12032-015-0618-7.

    Article 

    Google Scholar 

  • Terai S, Fushida S, Tsukada T, Kinoshita J, Oyama K, Okamoto K. Bone marrow derived “fibrocytes” contribute to tumor proliferation and fibrosis in gastric cancer. Gastric Cancer. 2015;18:306–13. https://doi.org/10.1007/s10120-014-0380-0.

    Article 
    PubMed 

    Google Scholar 

  • Ullah A, Wang K, Wu P, Oupicky D, Sun M.

    CXCR4-targeted liposomal mediated co-delivery of pirfenidone and AMD3100 for the treatment of TGFβ-induced HSC-T6 cells activation

    . Int J Nanomedicine. 2019;Volume 14:2927–44. https://doi.org/10.2147/IJN.S171280.

    Article 

    Google Scholar 

  • Chen Y, Huang Y, Reiberger T, Duyverman AM, Huang P, Samuel R, et al. Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen–positive myeloid cell infiltration in mice. Hepatology. 2014;59:1435–47. https://doi.org/10.1002/hep.26790.

    Article 
    PubMed 

    Google Scholar 

  • Thuya WL, Cao Y, Ho PC-L, Wong AL-A, Wang L, Zhou J, et al. Insights into IL-6/JAK/STAT3 signaling in the tumor microenvironment: Implications for cancer therapy. Cytokine Growth Factor Rev. 2025;85:26–42. https://doi.org/10.1016/j.cytogfr.2025.01.003.

    Article 
    PubMed 

    Google Scholar 

  • Li Y, Zhao J, Yin Y, Li K, Zhang C, Zheng Y. The role of IL-6 in fibrotic diseases: molecular and cellular mechanisms. Int J Biol Sci. 2022;18:5405–14. https://doi.org/10.7150/ijbs.75876.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Montero P, Milara J, Roger I, Cortijo J. Role of JAK/STAT in interstitial lung diseases; molecular and cellular mechanisms. Int J Mol Sci. 2021;22:6211. https://doi.org/10.3390/ijms22126211.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cortés AA, Diaz RA, Hernández-Campo P, Gorrochategui J, Primo D, Robles A, et al. Ruxolitinib in combination with prednisone and nilotinib exhibit synergistic effects in human cells lines and primary cells from myeloproliferative neoplasms. Haematologica. 2019;104:937–46. https://doi.org/10.3324/haematol.2018.201038.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Han C, Wang L-J, Dong Z-Q, Wang P-Y, Lv Y-W, Wang D, et al. Nintedanib alleviates chronic pancreatitis by inhibiting the activation of pancreatic stellate cells via the JAK/STAT3 and ERK1/2 pathways. Dig Dis Sci. 2023;68:3644–59. https://doi.org/10.1007/s10620-023-08052-7.

    Article 
    PubMed 

    Google Scholar 

  • Avsharian LC, Loganathan S, Ebelt ND, Shalamzari AF, Rodarte Muñoz I, Manuel ER. Tumor-colonizing E. coli expressing both collagenase and hyaluronidase enhances therapeutic efficacy of gemcitabine in pancreatic cancer models. Biomolecules. 2024;14:1458. https://doi.org/10.3390/biom14111458.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 2014;15:1243–53. https://doi.org/10.15252/embr.201439246.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Handorf AM, Yaxian Z, Matthew AH, Li W-J. Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression. Organogenesis. 2015;11:1–15. https://doi.org/10.1080/15476278.2015.1019687.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126:677–89. https://doi.org/10.1016/j.cell.2006.06.044.

    Article 
    PubMed 

    Google Scholar 

  • Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005;8:241–54. https://doi.org/10.1016/j.ccr.2005.08.010.

    Article 
    PubMed 

    Google Scholar 

  • Provenzano PP, Inman DR, Eliceiri KW, Keely PJ. Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK–ERK linkage. Oncogene. 2009;28:4326–43. https://doi.org/10.1038/onc.2009.299.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Morris BA, Burkel B, Ponik SM, Fan J, Condeelis JS, Aguirre-Ghiso JA, et al. Collagen matrix density drives the metabolic shift in breast cancer cells. EBioMedicine. 2016;13:146–56. https://doi.org/10.1016/j.ebiom.2016.10.012.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gunzer M, Schäfer A, Borgmann S, Grabbe S, Zänker KS, Bröcker E-B, et al. Antigen Presentation in Extracellular Matrix: Interactions of T Cells with Dendritic Cells Are Dynamic, Short Lived, and Sequential. Immunity. 2000;13:323–32. https://doi.org/10.1016/S1074-7613(00)00032-7.

    Article 
    PubMed 

    Google Scholar 

  • Dustin ML, de Fougerolles AR. Reprograming T cells: the role of extracellular matrix in coordination of T cell activation and migration. Curr Opin Immunol. 2001;13:286–90. https://doi.org/10.1016/S0952-7915(00)00217-X.

    Article 
    PubMed 

    Google Scholar 

  • Dustin ML, Choudhuri K. Signaling and polarized communication across the T cell immunological synapse. Annu Rev Cell Dev Biol. 2016;32:303–25. https://doi.org/10.1146/annurev-cellbio-100814-125330.

    Article 
    PubMed 

    Google Scholar 

  • Kuczek DE, Larsen AMH, Thorseth M-L, Carretta M, Kalvisa A, Siersbæk MS, et al. Collagen density regulates the activity of tumor-infiltrating T cells. J Immunother Cancer. 2019;7:68. https://doi.org/10.1186/s40425-019-0556-6.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rømer AMA, Thorseth M-L, Madsen DH. Immune modulatory properties of collagen in cancer. Front Immunol. 2021;12:791453. https://doi.org/10.3389/fimmu.2021.791453.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nicolas-Boluda A, Vaquero J, Vimeux L, Guilbert T, Barrin S, Kantari-Mimoun C, et al. Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment. Elife. 2021. https://doi.org/10.7554/eLife.58688.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhao Z, Li Q, Qu C, Jiang Z, Jia G, Lan G, et al. A collagenase nanogel backpack improves CAR-T cell therapy outcomes in pancreatic cancer. Nat Nanotechnol. 2025. https://doi.org/10.1038/s41565-025-01924-1.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Larsen AMH, Kuczek DE, Kalvisa A, Siersbæk MS, Thorseth M-L, Johansen AZ, et al. Collagen density modulates the immunosuppressive functions of macrophages. J Immunol. 2020;205:1461–72. https://doi.org/10.4049/jimmunol.1900789.

    Article 
    PubMed 

    Google Scholar 

  • Peng DH, Rodriguez BL, Diao L, Chen L, Wang J, Byers LA, et al. Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion. Nat Commun. 2020;11:4520. https://doi.org/10.1038/s41467-020-18298-8.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xu L, Shanlong W, Jufeng L, Jie L, Li B. Cancer immunotherapy based on blocking immune suppression mediated by an immune modulator LAIR-1. Oncoimmunology. 2020;9:1740477. https://doi.org/10.1080/2162402X.2020.1740477.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ramos MIP, Tian L, de Ruiter EJ, Song C, Paucarmayta A, Singh A, et al. Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction. Elife. 2021;10:e62927. https://doi.org/10.7554/eLife.62927.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Piper M, Mueller AC, Karam SD. The interplay between cancer associated fibroblasts and immune cells in the context of radiation therapy. Mol Carcinog. 2020;59:754–65. https://doi.org/10.1002/mc.23205.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Oncogenic collagen I homotrimers from cancer cells bind to α3β1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer. Cancer Cell. 2022;40:818–834.e9. https://doi.org/10.1016/j.ccell.2022.06.011

  • Dwyer AR, Truong TH, Ostrander JH, Lange CA. 90 years of progesterone: steroid receptors as MAPK signaling sensors in breast cancer: let the fates decide. J Mol Endocrinol. 2020. https://doi.org/10.1530/JME-19-0274.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lebbink RJ, de Ruiter T, Adelmeijer J, Brenkman AB, van Helvoort JM, Koch M, et al. Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR-1. J Exp Med. 2006;203:1419–25. https://doi.org/10.1084/jem.20052554.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • A Study of PEGylated Recombinant Human Hyaluronidase in Combination With Nab-Paclitaxel Plus Gemcitabine Compared With Placebo Plus Nab-Paclitaxel and Gemcitabine in Participants With Hyaluronan-High Stage IV Previously Untreated Pancreatic Ductal Adenocarcinoma https://clinicaltrials.gov/study/NCT02715804?cond=PDAC%20-%20Pancreatic%20Ductal%20Adenocarcinoma&intr=PEGPH20&rank=7. 2025.

  • Maneval DC, L. Caster C, Derunes C, Locke KW, Muhsin M, Sauter S, et al. Pegvorhyaluronidase alfa. Polymer-Protein Conjugates. Elsevier; 2020; 175–204. https://doi.org/10.1016/B978-0-444-64081-9.00009-7

  • Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69:562–73. https://doi.org/10.1016/j.cardiores.2005.12.002.

    Article 
    PubMed 

    Google Scholar 

  • Bond MD, Van Wart HE. Characterization of the individual collagenases from Clostridium histolyticum. Biochemistry. 1984;23:3085–91. https://doi.org/10.1021/bi00308a036.

    Article 
    PubMed 

    Google Scholar 

  • Mandl I, Zipper H, Ferguson LT. Clostridium histolyticum collagenase: its purification and properties. Arch Biochem Biophys. 1958;74:465–75. https://doi.org/10.1016/0003-9861(58)90017-1.

    Article 
    PubMed 

    Google Scholar 

  • Fágáin CÓ. Understanding and increasing protein stability. Biochimica et Biophysica Acta (BBA). 1995;1252:1–14. https://doi.org/10.1016/0167-4838(95)00133-F.

    Article 
    PubMed 

    Google Scholar 

  • Tran S, DeGiovanni P-J, Piel B, Rai P. Cancer nanomedicine: a review of recent success in drug delivery. Clin Transl Med. 2017;6:44. https://doi.org/10.1186/s40169-017-0175-0.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Raj S, Khurana S, Choudhari R, Kesari KK, Kamal MA, Garg N, et al. Specific targeting cancer cells with nanoparticles and drug delivery in cancer therapy. Semin Cancer Biol. 2021;69:166–77. https://doi.org/10.1016/j.semcancer.2019.11.002.

    Article 
    PubMed 

    Google Scholar 

  • Foley CJ, Luo C, O’Callaghan K, Hinds PW, Covic L, Kuliopulos A. Matrix metalloprotease-1a promotes tumorigenesis and metastasis. J Biol Chem. 2012;287:24330–8. https://doi.org/10.1074/jbc.M112.356303.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cao J, Chiarelli C, Kozarekar P, Adler HL. Membrane type 1-matrix metalloproteinase promotes human prostate cancer invasion and metastasis. Thromb Haemost. 2017;93:770–8. https://doi.org/10.1160/TH04-08-0555.

    Article 

    Google Scholar 

  • Kudo Y, Iizuka S, Yoshida M, Tsunematsu T, Kondo T, Subarnbhesaj A, et al. Matrix metalloproteinase-13 (MMP-13) directly and indirectly promotes tumor angiogenesis*. J Biol Chem. 2012;287:38716–28. https://doi.org/10.1074/jbc.M112.373159.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Radisky ES, Radisky DC. Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer. J Mammary Gland Biol Neoplasia. 2010;15:201–12. https://doi.org/10.1007/s10911-010-9177-x.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Eble JA, Niland S. The extracellular matrix in tumor progression and metastasis. Clin Exp Metastasis. 2019;36:171–98. https://doi.org/10.1007/s10585-019-09966-1.

    Article 
    PubMed 

    Google Scholar 

  • Bayer SV, Grither WR, Brenot A, Hwang PY, Barcus CE, Ernst M, et al. DDR2 controls breast tumor stiffness and metastasis by regulating integrin mediated mechanotransduction in CAFs. Elife. 2019. https://doi.org/10.7554/eLife.45508.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Akinjiyan FA, Ibitoye Z, Zhao P, Shriver LP, Patti GJ, Longmore GD, et al. DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression. Oncogene. 2024;43:189–201. https://doi.org/10.1038/s41388-023-02884-3.

    Article 
    PubMed 

    Google Scholar 

  • Jung E, Kim TY, Han J, Lee KY, Shin SY. TLR2–EGR1 signaling axis modulates TGFβ1-induced differentiation of fibroblasts into myofibroblasts in pulmonary fibrosis. Biochem Biophys Res Commun. 2024;736:150836. https://doi.org/10.1016/j.bbrc.2024.150836.

    Article 
    PubMed 

    Google Scholar 

  • Diehm YF, Jost Y, Kotsougiani-Fischer D, Haug V, Splinter M, Häring P, et al. The treatment of capsular contracture around breast implants induced by fractionated irradiation: the collagenase of the bacterium Clostridium histolyticum as a novel therapeutic approach. Aesthet Plast Surg. 2021;45:1273–81. https://doi.org/10.1007/s00266-020-01970-1.

    Article 

    Google Scholar 

  • Alkasalias T, Moyano-Galceran L, Arsenian-Henriksson M, Lehti K. Fibroblasts in the tumor microenvironment: shield or spear? Int J Mol Sci. 2018;19:1532. https://doi.org/10.3390/ijms19051532.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Høye AM, Erler JT. Structural ECM components in the premetastatic and metastatic niche. Am J Physiol Cell Physiol. 2016;310:C955–67. https://doi.org/10.1152/ajpcell.00326.2015.

    Article 
    PubMed 

    Google Scholar 

  • Mohan V, Das A, Sagi I. Emerging roles of ECM remodeling processes in cancer. Semin Cancer Biol. 2020;62:192–200. https://doi.org/10.1016/j.semcancer.2019.09.004.

    Article 
    PubMed 

    Google Scholar 

  • Okada M, Oba Y, Yamawaki H. Endostatin stimulates proliferation and migration of adult rat cardiac fibroblasts through PI3K/Akt pathway. Eur J Pharmacol. 2015;750:20–6. https://doi.org/10.1016/j.ejphar.2015.01.019.

    Article 
    PubMed 

    Google Scholar 

  • Favreau AJ, Vary CPH, Brooks PC, Sathyanarayana P. Cryptic collagen IV promotes cell migration and adhesion in myeloid leukemia. Cancer Med. 2014;3:265–72. https://doi.org/10.1002/cam4.203.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mierke CT. Extracellular matrix cues regulate mechanosensing and mechanotransduction of cancer cells. Cells. 2024;13:96. https://doi.org/10.3390/cells13010096.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pankova D, Jiang Y, Chatzifrangkeskou M, Vendrell I, Buzzelli J, Ryan A, et al. RASSF 1A controls tissue stiffness and cancer stem-like cells in lung adenocarcinoma. EMBO J. 2019. https://doi.org/10.5252/embj.2018100532.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Continue Reading