Mitochondria-targeted nanosystems in the treatment of central nervous

Introduction

When mitochondria are mentioned, their name comes to mind naturally as “powerhouse”. As is well known, they are semi-autonomous organelles enclosed by two membranes, possessing own genetic material and found in most eukaryotic cells. Mitochondria provide adenosine triphosphate (ATP) to cells and serve as the primary site for aerobic respiration, with a diameter of approximately 0.5 to 1 micrometer.^1,2 ATP production occurs through oxidative phosphorylation (OXPHOS) and the tricarboxylic acid (TCA) cycle. In the inner mitochondrial membrane, the electron transport chain (ETC) transfers electrons from reduced coenzymes (NADH and FADH₂) to oxygen, driving proton pumps to form a transmembrane proton gradient, which ultimately synthesizes ATP through ATP synthase.^3,4 Mitochondria are not only the centers of energy metabolism but also participate in various cellular processes such as calcium ion homeostasis, apoptosis, and reactive oxygen species (ROS) regulation.^5,6 They play a dual role in maintaining physiological homeostasis and mediating pathological damage, thereby determining the survival and death of cells. Mitochondrial dysfunction, characterized by oxidative stress, abnormal energy metabolism, and impaired apoptosis, is a key pathological mechanism in neurodegenerative diseases, cancer, and cardiovascular and kidney disorders. Under pathological conditions, ETC dysfunction leads to energy crises and ROS surges, while mitochondrial dynamics imbalance (abnormal fusion/fission) and autophagy defects contribute to neurodegeneration. Studies have shown that the frequency and duration of the mitochondrial permeability transition pore (mPTP) opening are correlated with increased ROS production, electron leakage, and a reduction in mitochondrial membrane potential (MMP), collectively precipitating cellular apoptosis.⁷ Zhou et al discovered that the transcription factor Nynrin is highly expressed in hematopoietic stem cells, with further upregulation under stress conditions such as radiation. Nynrin serves as a key regulator in maintaining HSCs by modulating mitochondrial function. Deficiency of Nynrin leads to a reduction in HSC numbers, loss of quiescence, impaired self-renewal capacity, and mitochondrial dysfunction characterized by increased mPTP opening, mitochondrial swelling, and elevated ROS levels.⁸ Strategies targeting MMP restoration, mtDNA protection, regulate the opening of mPTP, and quality control pathway activation offer novel therapeutic avenues.⁹

Central nervous system (CNS) diseases, including neurodegenerative diseases, brain tumors, and cerebrovascular lesions, pose significant global public health challenges due to their high disability and mortality rates.^10–12 The common pathological features of these diseases are closely related to mitochondrial dysfunction. For instance, mitochondria in the brain of patients with Alzheimer’s disease (AD) differ significantly in number and morphology from those in healthy individuals.¹³ Amyloid-β (Aβ) oligomers in the brains of AD patients induce abnormal opening of the mPTP, leading to calcium overload and neuronal apoptosis.^14,15 In Parkinson’s disease (PD), abnormal α-synuclein aggregation disrupts mitophagy, leading to accumulated damaged mitochondria in dopaminergic neurons.^16,17 Post-stroke ischemia-reperfusion generates excessive ROS that directly damages mtDNA, exacerbating neuronal death.^18,19 These findings collectively underscore mitochondria as central targets for treating CNS diseases.

Nano-drug delivery systems have emerged as key tools for CNS therapy, enhancing drug bioavailability and retention while enabling site-specific delivery via modifications with peptides, membranes, or microenvironment-responsive ligands.^20,21 Notably, due to the presence of blood-brain barrier (BBB), over 98% of small-molecule drugs and nearly all large-molecule therapeutics struggle to effectively reach brain lesions. Therefore, precise mitochondrial interventions in CNS diseases face dual challenges, including overcoming the BBB’s biological bottleneck, and further achieving subcellular-level precision delivery.²² Most previous studies have reviewed the strategies for nanomaterials crossing the BBB, which could be achieved via carrier, receptor or cell-mediated transcytosis, as well as some external modulation strategies.^23–25 Mitochondria-targeted nanosystems are emerging as promising therapeutic approaches for mitochondria-related disorders treatment.^26–28 These nanosystems have the potential to directly deliver drugs to mitochondria, reduce oxidative stress of mitochondria, and restore energy homeostasis.²⁹

This review discusses the design principles and applications of mitochondria-targeted nanosystems, with a focus on their use in CNS diseases (Figure 1). We aim to provide insights for researchers in mitochondrial-targeted therapy and inspire future designs of precision delivery platforms.

Figure 1 Schematic illustration of mitochondria-targeted nanosystems in CNS disorders. (A) Mitochondrial function and mitochondria-targeted approaches. (B) The microenvironment of mitochondria-related CNS diseases. (C) The role of mitochondria-targeted nanosystems in regulating the mitochondria function. Created with BioRender.com.

Design Principles and Applications of Mitochondria-Targeted Nanosystems

Mitochondria have a double-membrane structure consisting of the outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM). Both membranes are primarily composed of proteins and lipids. The space between them is termed the inter-membrane space (IMS), while the IMM is subdivided into the inner boundary membrane (IBM), cristae junctions (CJs), and cristae.³⁰ Porins (eg, VDAC) are abundant on the OMM, allowing free diffusion of substances <5 kDa. In contrast, the IMM exhibits extremely low permeability and high tortuosity with only specific molecules (such as O₂, CO₂) passively diffusing while other substances rely on transport proteins. Located in the IMM, the mPTP is a non-selective channel formed by large protein complexes. It critically regulates apoptosis—aberrant opening mediates leakage of pro-apoptotic factors (eg, Cytochrome C/Cyt C) from the IMS into the cytoplasm, activating apoptotic cascades. The IMM also houses oxidative phosphorylation machinery and is enriched with cardiolipin, a phospholipid essential for OXPHOS complex stability.³¹

Mitochondria-targeted nanosystems usually employ four key strategies, namely (1) small-molecule ligands (eg, triphenylphosphonium/TPP), which exploit the IMM’s negative membrane potential to accumulate drugs in the matrix; (2) peptide ligands that leverage lipophilicity/cationic properties; (3) mitochondrial membrane-derived vesicles; and (4) biomimetic membrane systems. The latter two utilize natural membrane components (eg, proteins, lipids) for intrinsic homing to mitochondria. Herein, we discuss the design principles of these nanosystems and summarize their applications (Table 1).

Table 1 Representative Mitochondria-Targeted Groups

Small Molecules

TPP

Owing to the transmembrane potential (Δψm) of −150 to −180 mV (matrix negative relative to cytoplasm) across the IMM, lipophilic cations accumulate in the mitochondrial matrix via electrophoresis. Their delocalized surface charge enables lipid bilayer penetration, driving selective enrichment via the electrochemical gradient.^32,60

Meanwhile, the unique electrochemical properties of mitochondria provide feasibility for the targeted delivery of antioxidant molecules. This is achieved by chemically coupling therapeutic molecules with lipophilic cations, which enables selective accumulation through the membrane potential of mitochondria, thereby establishing a specific protective mechanism against mitochondrial oxidative damage.^32,61 TPP, as a targeting moiety, delivers various antioxidants into mitochondria and accumulates within mitochondrial organelles. As one of the most common mitochondria-targeted molecules, TPP is an organophosphate compound with a lipophilic cation that can effectively target mitochondria through electrostatic interactions. The key mechanism behind its targeting strategy stems from the electrochemical characteristics of the IMM.⁶² So far, research on using TPP as a mitochondria-targeted modification has been extensive. TPP can be modified on various nanocarriers such as liposomes, inorganic nanoparticles, micelles, and other polymer nanoparticles. A common strategy for modifying liposomes with TPP involves synthesizing TPP-PEG-PE or TPP-PEG-DSPE first to improve the stability and targeting efficiency of the carrier by coupling it with other groups. When inorganic nanoparticles are used as carriers, the modification methods usually include direct coupling and indirect modification techniques. Inorganic nanoparticles featuring -COOH, -NH₂, or -SH groups on their surface are suitable for direct coupling. For example, Xia et al³³ utilized TPP coupled with DSPE-TK-PEG2000 to achieve mitochondrial targeting and demonstrated ROS-responsive effects via the thioketal (TK) bond. They developed a drug delivery system using nanoliposomes to deliver tripterygium glycoside to mitochondria for treating hepatocellular carcinoma. It was shown that modifying the liposome surface with TPP-PEG2000-TK-DSPE could significantly enhance the aggregation ability of these liposomes in mitochondria. Li et al synthesized TPP-modified micelles loaded with puerarin for the treatment of acute myocardial infarction, they likewise began by synthesizing the mitochondriotropic polymer TPP-PEG-PE. Compared to free puerarin, these micelles exhibited enhanced cellular uptake, improved mitochondrial targeting, and increased lysosomal escape.³⁴ However, this method requires multi-step organic synthesis, more complex preparation processes and higher costs. In Gu et al’s study³⁵ bimetallic cluster nanozymes were employed to reduce neuropathic pain. TPP was pre-modified to TPP-COOH and then covalently linked to the surface of bimetallic cluster nanozymes. Covalent bonds give it high stability and prevent TPP from detaching in the internal environment. Nevertheless, it is important to note that TPP is inherently a cationic species. High-density TPP modification also carries potential toxicity, as it may disrupt mitochondrial membrane integrity, thereby impairing the respiratory chain and ATP synthesis. This cascade of events can ultimately lead to cellular dysfunction or apoptosis. Furthermore, TPP may exhibit metabolic instability in vivo and has a limited ability to cross the blood-brain barrier, posing a significant challenge for treating brain disorders.^63,64

Besides TPP, other antioxidants, including ubiquinol, alpha-tocopherol, vitamin C, metformin, and tempol, have also been investigated.^32,65,66 The combination of lipophilic cations and antioxidants is applied in the treatment of various diseases, such as chronic obstructive pulmonary disease, traumatic brain injury, inflammatory bowel disease, cardiovascular diseases, renal ischemia-reperfusion injury, PD, AD.^67–73

Other Cationic Targeting Molecules

Rhodamine, initially discovered as a dye in 1887, was later utilized as a probe.⁷⁴ Rhodamine 123 belongs to the rhodamine dye family and is a lipophilic cationic compound that accumulates in mitochondria in a mitochondrial membrane potential-dependent manner, serving as a fluorescent probe for monitoring membrane potential in living cells. Later, it was also gradually used for mitochondria-targeted modifications. Similar to TPP, it can be linked to drugs through chemical coupling or modified liposomes, polymer nanoparticles, and other carriers in a similar fashion.^36,37,75,76

Another derivative of rhodamine, tetramethyl rhodamine methyl ester (TMRM), functions similarly to Rhodamine 123. Its structure includes a tetramethyl-substituted rhodamine skeleton with methyl ester groups. As a cationic dye, TMRM enriches in the mitochondrial matrix with a higher negative potential through electrochemical gradients, and its fluorescence signal can quantitatively reflect changes in MMP.^40,77–79 TMRM can be conjugated to other molecules, such as polymers and drugs, through functional group reactions to form functional probes or drug delivery systems. Additionally, F16 and its analogs are used for mitochondrial tracing and serve as mitochondria-targeted anticancer agents, primarily effective against cancer.^80–82 F16 is mainly conjugated to drug molecules through chemical synthesis, thereby enhancing its mitochondrial targeting and antitumor activity.^41,83

Moreover, dequalinium (DQA) is another cationic mitochondria-targeted molecule—a bis-quaternary ammonium compound with two positively charged quaternary ammonium groups and a hydrophobic carbon chain, combining hydrophilicity with hydrophobicity. DQA can be used in nanoemulsions or liposome assemblies.^84–86 A distinctive application of DQA is its ability to self-assemble in aqueous solution to form vesicular structures known as DQAsomes, which are used for the delivery of genes or small-molecule drugs.⁸⁷ DQA can be covalently linked directly with lipids, such as DSPE-PEG, modified on the surface of liposomes, and form mitochondria-targeted carriers. In polymer nanoparticles, such as polylactic acid-glycolic acid copolymer, DQA binds to the carriers through electrostatic interactions or chemical coupling.^43,88 Although these small molecules exhibit good mitochondria-targeting abilities, their potential toxicity due to their cationic properties limits their further applications.⁸⁹

Mitochondria-Targeted Peptides

SS Peptides (with SS-31 as a Representative)

Mitochondria-targeted peptides (MTPs) are short peptides engineered to deliver therapeutics or modulate mitochondrial functions. Their design leverages mitochondrial membrane properties or natural targeting signals. Szeto-Schiller (SS) peptides, exemplified by tetrapeptides with alternating aromatic (eg, phenylalanine and tyrosine) and basic (eg, lysine and arginine) residues, exhibit potent molecular recognition and membrane penetration.⁹⁰ They specifically target the IMM via lipophilic-cationic structures and confer mitochondrial protection through dual mechanisms.⁹¹ On the one hand, they can directly eliminate mitochondrial ROS and inhibit their excessive generation. On the other hand, SS peptides can maintain mitochondrial membrane integrity by blocking pathological mPTP opening. Critically, SS peptides mitigate apoptosis and necrosis triggered by oxidative stress or ETC dysfunction,demonstrating efficacy in ischemia-reperfusion, neurodegeneration (AD/PD), cognitive deficits, and renal fibrosis models with high biocompatibility.^91,92 Szeto-Schiller Peptide 31 (SS-31, also known as MTP-131, elamipretide), a representative aromatic cationic peptide, selectively binds cardiolipin on the IMM via electrostatic interactions driven by its alternating cationic/aromatic structure.^58,93–96 This targeting mechanism operates independently of strict membrane potential dependence. SS-31 is frequently conjugated to nanocarriers (eg, liposomes, micelles, or polymer nanoparticles) to enhance mitochondrial targeting efficiency through the synergistic effect of passive targeting of nanocarriers (eg, enhanced permeability and retention effect) and active targeting of SS-31.^97–99 Methods for conjugating it to nanocarriers primarily include covalent connection and hydrophobic insertion. For example, in polymer nanoparticles, SS-31 can be connected to the particle surface through chemical coupling of amino or carboxyl groups (such as EDC/NHS reaction). It is also possible to covalently link the cysteine residues on SS-31 with DSPE-PEG₂₀₀₀-Mal (maleimide group) in the liposome formulation through thioether bonds.^{48,49,100,101} SS-31 has a favorable safety profile and is considered a promising strategy for the treatment of diabetic cardiomyopathy. Xiong et al revealed a novel mechanism of mitochondria-targeted peptide SS-31 for the treatment of diabetic cardiomyopathy (DCM): SS-31 inhibits mitochondrial lipid peroxidation and attenuates mitochondria-dependent ferroptosis through specific activation of mitochondrial glutathione peroxidase 4 (mitoGPX4). In a diabetic cardiomyopathy model, high glucose and metabolic disorders lead to enhanced mitochondrial oxidative stress, imbalanced iron metabolism, and reduced mitoGPX4 activity, which in turn triggers ferroptosis in cardiomyocytes. SS-31 restored the antioxidant function of mitoGPX4 by targeting mitochondria and stabilizing the structure of cardiolipin, reduced mitochondrial ROS and lipid peroxidation accumulation, as well as inhibited the expression of key markers of ferroptosis, thereby protecting cardiomyocytes from ferroptosis-driven injury. The experimental results showed that SS-31 significantly improved cardiac function, attenuated myocardial fibrosis and mitochondrial structural disruption in diabetic mice, and provided a novel strategy for targeting mitochondrial ferroptosis in the treatment of DCM.¹⁰² In addition, Zhu et al summarized that, as a mitochondria-targeted antioxidant, SS-31 alleviates oxidative stress by inhibiting the overproduction of mitochondrial ROS, repairing the function of the mitochondrial electron transport chain to enhance ATP synthesis, inhibiting mitochondrial membrane permeability transition pore opening and down-regulating inflammatory factors expression, thereby reducing oxidative stress damage to renal tubular epithelial cells and podocytes, as well as attenuating renal inflammatory responses, suggesting that SS-31 may be a candidate for the treatment of mitochondria-associated nephropathy, providing a new direction in the treatment of nephropathy.¹⁰³ Currently, SS-31 has been widely used in the treatment of mitochondrial dysfunction-related diseases in various systems, such as the nervous and cardiovascular systems. Du et al systematically explored the mechanism of action and efficacy of the novel mitochondria-targeted antioxidant peptide SS-31 in alleviating mitochondrial dysfunction, highlighting the broad prospects of SS-31 as a therapeutic tool for precisely regulating mitochondrial function in the treatment of mitochondrial-related diseases.¹⁰⁴ Furthermore, many nano-delivery systems utilize the mitochondria-targeting ability of SS-31 to deliver drugs, genes or probes to the mitochondria in a targeted manner, which synergistically enhances the repairing effect on mitochondrial dysfunction with the delivered agents, reduces systemic toxicity and improves the bioavailability.^{49,50,105–107}

XJB-5-131

XJB-5-131 is also a synthetic peptide and a mitochondrial-targeted antioxidant. Its structural design combines mitochondrial targeting and free radical scavenging functions. The molecular structure of XJB-5-131 is composed of two functional modules linked by chemical bonds. The mitochondrial-targeting moiety is a cationic oligopeptide structurally inspired by gramicidin S. It targets the negatively charged regions of the mitochondrial inner membrane via positively charged amino acid residues and binds to phosphatidylserine in the mitochondrial inner membrane through electrostatic interactions. The antioxidant active part is composed of nitroxide radicals. Usually, the targeted peptide is coupled with the antioxidant group through ester bonds or amide bonds to ensure the structural stability and functional synergy.^{54,55,108,109} It targets mitochondria more rapidly and does not require a carrier, showing low toxicity and little interference with MMP. Besides, it is mainly utilized in relation to oxidative stress diseases, with its application in drug delivery being less explored and requiring further development.¹¹⁰ It has been shown, XJB-5-131 is a novel mild oxidative phosphorylation uncoupler that partially disrupts the proton gradient in the IMM, thereby reducing ATP synthesis efficiency and increasing heat production, thus regulating mitochondrial energy metabolism.⁵⁴ Unlike potent uncoupling agents, XJB-5-131 exhibits controllable uncoupling effects at low doses, reducing ROS accumulation and alleviating oxidative stress damage while avoiding side effects such as excessive heat production and energy depletion. Experiments have shown that this compound selectively acts on mitochondrial membrane structures to improve cellular energy metabolism disorders and has demonstrated protective potential in models of neurodegenerative diseases and ischemic reperfusion injury. Its “mildness” makes it safer for treating metabolic syndrome and age-related diseases, but further research is needed on its long-term effects, tissue specificity, and clinical translation potential. Sun et al found that the mitochondria-targeting compound XJB-5-131 restored Pebp1 protein expression in chondrocytes, inhibiting ferroptosis (reducing lipid peroxidation products and upregulating GPX4 activity), thus protecting chondrocytes and alleviating osteoarthritis (OA) progression; in vivo experiments showed that XJB-5-131 joint injection significantly reduced cartilage degeneration and inflammation in mouse OA models with a favorable safety profile, providing a new strategy for OA treatment targeting ferroptosis.¹¹¹

Mitochondrial-Penetrating Peptides, MPPs

Mitochondrial-penetrating peptides (MPPs) have been extensively studied as a means of mitochondrial uptake. MPPs are synthetic mitochondria-targeted peptides whose typical structure consists of 4–16 amino acid residues, which typically contain positively charged basic and hydrophobic amino acids. Studies have shown that the mitochondrial targeting efficiency of MPPs is closely related to their surface positive charge properties and hydrophobicity. MPPs, as a type of short peptides with the ability to penetrate both cellular and mitochondrial membranes, present diversified strategies in their mechanism of action and structural design. Innovative strategies based on the structural similarity between mitochondria and bacterial membranes have attracted attention, such as semi-Grammycin analogues designed to simulate Grammycin S. MPPs relies on the characteristics of positively charged amino acids and achieves delivery through interaction with negatively charged mitochondrial membranes, which can enhance the precise accumulation of drugs in mitochondria and reduce off-target effects.^27,32,112 Zhou et al successfully developed a polymer-MPP-doxorubicin (P-M-Dox) coupling that achieved specific mitochondrial delivery through mitochondria-targeting properties and significantly improved doxorubicin delivery efficiency by circumventing the P-gp efflux pump effect.¹¹³

Advantages and Challenges of MTPs

Peptides targeting mitochondria have advantages such as high targeting efficiency, biocompatibility and stability, and avoiding the risk of genomic integration.^114–116 However, several concerns should be addressed issues. The mitochondrial targeting of some peptides mainly depends on the electrochemical potential of the electron transport chain, which may fail under pathological conditions (such as reduced membrane potential). Additionally, peptides tend to dissociate after binding to mitochondria, affecting sustained action. Off-target effects may also occur, as peptides may non-specifically bind to other negatively charged cellular structures or interfere with normal mitochondrial function. Furthermore, large-scale production is challenging.^112,115,117 There is still room for improvement in terms of structure, joint delivery systems, and dynamic response design.^96,118,119

Mitochondria-Targeted Vesicles and Mitochondrial Membrane Mimetic Systems

MITO-Porter is a liposome-based mitochondrial targeting delivery system that encapsulates drugs in double-layer liposomes and is surface-modified with mitochondrial targeting ligands (such as mitochondrial signaling peptides or membrane fusion-related lipids), to achieve mitochondrial delivery.⁵⁷ The MITO-Porter system has been widely utilized in the field of mitochondrial targeting.¹²⁰ The core principle behind MITO-Porter’s mitochondrial targeting lies in achieving specific delivery through the membrane fusion mechanism of lipid nanoparticles. It adopts a bilayer liposome structure, where surface-modified ligands (eg, octaarginine/R8) mediate binding to the outer mitochondrial membrane (OMM), followed by liposome-OMM fusion, which directly releases the cargo into the intermembrane space.^121–123 This mechanism overcomes the physical barrier posed by the mitochondrial bilayer membrane structure and avoids lysosomal degradation via the endocytosis pathway.²⁶ Yuma Yamada et al demonstrated mitochondrial gene therapy using MITO-Porter-encapsulated tRNA nanoparticles composed of DOPE, sphingomyelin, and stearylated R8 at a molar ratio of 9:2:1.¹²⁴ However, its poor stability, limited drug loading capacity, and difficulty in delivering hydrophilic drugs restrict further applications.⁵⁸

Biomimetic cell membrane encapsulation technology, which leverages the integration of natural membrane components and targeting mechanisms, has emerged as a promising approach to address these limitations.^125–127 Specifically, biomimetic cell membranes can confer immune evasion, prolonged circulation, and precise targeting capabilities on nanoparticles, thereby significantly enhancing delivery efficiency and reducing off-target effects.¹²⁸ This biomimetic design not only retains the characteristics of natural membranes but also overcomes the spatial resolution limitations of traditional delivery systems through biocompatible transport pathways.^129–132 Compared to whole cell membranes, mitochondria-derived membrane-coated nanosystems can deliver therapeutic molecules to mitochondria more efficiently, enabling precise subcellular-level drug delivery through membrane fusion-mediated intracellular transport mechanisms.⁵⁸ The extraction of mitochondrial membranes from cells typically involves two steps: first, cells are homogenized using a glass homogenizer; then, mitochondria are isolated via gradient centrifugation. Finally, mitochondrial membranes are obtained by ultracentrifugation at low temperature.^59,133 By leveraging the natural properties of mitochondrial membranes to achieve homologous targeting, existing research has explored methods for directly wrapping nanoparticles with membranes to enhance targeting, including co-extrusion and sonication.^134–137 Chen et al reported a mitochondrial-mimicking therapeutic strategy capable of specifically targeting dilated cardiomyopathy and effectively regulating mitochondrial homeostasis.¹³⁸ They synthesized nano-micelles (TPTN) and achieved mitochondrial targeting in cardiomyocytes by encapsulating the micelles with OMM-derived vesicles. The surface of MTPTN is functionalized with OMM-specific proteins, which enable direct homophilic binding to their counterparts on the mitochondrial membrane of cardiomyocytes. This membrane-membrane recognition mechanism significantly enhances targeting specificity. In addition, by combining two types of membranes through methods such as sonication, extrusion, or a combination of both, multifunctional hybrid membranes can be constructed that integrate the inherent properties of both components.^139,140 Shi et al developed hybrid membranes using cancer cell membranes and mitochondrial membranes to achieve dual targeting.⁵⁹ Mitochondrial membrane proteins integrated into the hybrid membranes—such as the outer membrane protein TOM20 and mitochondrial fusion-related proteins—mimic the natural surface features of mitochondria, promoting either membrane fusion or endogenous uptake between nanoparticles and mitochondria, thereby enabling subcellular organelle-level targeting. The inner and outer mitochondrial membranes contain various proteins and lipids that can be used for homologous targeting and lipid fusion. Targeted delivery using membrane-coated nanocarriers or membrane-fused liposomes can facilitate homologous targeting via antibody-antigen interactions.

Moreover, in addition to effectively deliver the therapeutics to mitochondria, some vesicles also have the property to rescue the mitochondrial dysfunction. Deng et al have proposed that the extracellular vesicles collected from mesenchymal stem cells (MSCs) with 3D dynamic culture could improve the proliferation ability and cell viability of aging-gingival MSCs, as well as ameliorate senescence. This effects was attributed to the up-regulated genes which were related to the mitochondrial dynamics, cell cycle and DNA repair functions.¹⁴¹

Mitochondria-Targeted Nanosystems for CNS Disorders

Given the central role of mitochondria in cellular energy homeostasis, mitochondria-targeted nanosystems show therapeutic potential for mitochondrial-related pathologies such as cancer, cardiovascular diseases, and brain disorders.^142,143 The substantial accumulation of nanoparticles in a subset of mitochondria disrupts mitochondrial network connectivity by inducing fragmentation, impairs calcium buffering capacity through persistent mPTP opening, and activates retrograde signaling to the nucleus via released ROS and Mitochondrial DNA (mtDNA). This mechanism can be therapeutically harnessed to either trigger apoptosis in cancer cells or protect neurons in neurodegenerative diseases by modulating mitochondrial function.^144,145 These nanosystems exert therapeutic effects by modulating energy metabolism, targeting mitochondrial DNA, regulating ROS, directing mitochondrial proteins, exerting anti-inflammatory effect, or enhancing mitophagy.^146,147 Compared with other organs, the brain is more sensitive and reliant on energy produced by mitochondria. Additionally, nearly 15% of global deaths are closely related to mitochondrial damage in brain diseases.¹⁴⁸ This section discusses applications of mitochondrial-targeted nanosystems in CNS disorders, including neurodegenerative diseases, brain tumors, and ischemic stroke (Table 2).

Table 2 Mitochondria-Targeted Nanosystems in CNS Disorders

Before achieving the mitochondria of CNS-related cells, these nanosystems should bypass the first barrier of BBB. Recently, a variety of transport therapeutics have been developed for enhancing the BBB crossing ability of nanosystems, including adsorptive-mediated transcytosis, carrier-mediated transcytosis, receptor-mediated transcytosis, cell-mediated transcytosis, and modulation of tight junction.^180,181 However, the specific diseased BBB-based brain-targeting strategies should be designed based on the BBB evolutions of CNS diseases, which owing to that the diseased BBB of various CNS disorders is different and complex.

Neurodegenerative Diseases

Neurodegenerative diseases, including AD, PD, Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are a group of heterogeneous disorders caused by the progressive degeneration of neurons.¹⁸² Mitochondrial dysfunction is closely associated with the progression of neurodegenerative diseases, leading to oxidative stress and impaired neuronal metabolic activity.¹⁸³ Consequently, mitochondria represent a promising target for therapies aimed at mitigating neurodegeneration. In recent years, various mitochondria-targeted nanosystems have been developed to modulate mitochondrial functions in neurodegenerative diseases, such as regulating calcium ion transport, delivering antioxidants, chelating metals, and modifying proteins.¹⁸⁴

AD

As the most common neurodegenerative disease, AD is characterized by pathological aggregation of Aβ plaques and hyperphosphorylated Tau neurofibrillary tangles, as well as abnormally elevated ROS, which are primarily produced in mitochondria.¹⁸⁵ Notably, hyperphosphorylated Tau exacerbates mitochondrial damage by generating excessive ROS and promoting mitochondrial fission. Conversely, mitochondrial oxidative stress also promotes abnormal phosphorylation and aggregation of Tau protein.¹⁸⁶ Hence, targeting mitochondria and alleviating mitochondrial dysfunction are critical strategies for treating AD.

Various mitochondria-targeted nanosystems have been employed in AD treatment, designed with mitochondria-targeting peptides (such as TPP and SS-31) and loaded with therapeutic agents (eg, curcumin, resveratrol, methylene blue, etc).^{149–153,155,186} Ceria (CeO₂) nanoparticles, widely studied for their potential ROS-scavenging activity through shuttling between Ce³⁺ and Ce⁴⁺ oxidation states, have been modified to target mitochondria. Kwon et al designed TPP-conjugated CeO₂ nanoparticles (TPP-ceria NPs) that could specifically target mitochondria and suppress neuronal death in an AD mouse model.¹⁵⁶ After TPP modification, significantly higher mitochondrial localization was observed in SH-SY5Y cells treated with FITC-TPP-ceria NPs compared to FITC-ceria NPs. Moreover, TPP-ceria NPs markedly inhibited Aβ-induced mitochondrial ROS production and reduced reactive gliosis and morphological mitochondrial damage, demonstrating that mitochondrial therapeutics hold promise for AD treatment. Li et al have also utilized TPP to modify tetrahedral DNA framework-based nanoparticles (TDFNs) for mitochondria-targeting, as well as cholesterol for BBB crossing and antisense oligonucleotide (ASO) for diagnosis and gene silencing therapy of AD.¹⁸⁷ The results showed the efficient colocalization of TDFNs and MitoTracker Red in neuron cells, demonstrating the superior mitochondia-targeted ability of TDFNs.

In contrast to TPP, the SS-31 peptide not only targets neurons and mitochondria but also directly alleviates mitochondrial dysfunction and oxidative damage.¹⁸⁸ Specifically, SS-31 has shown beneficial effects in treating AD^189–191 and has been conjugated with cyclosporin A (CsA) via a TK bond (Figure 2).⁹⁸ The resulting self-assembled micelles (CsA-TK-SS-31, abbreviated as CTS) efficiently targeted the mitochondria of damaged neurons and microglia driven by SS-31. Upon exposure to high levels of ROS within mitochondria, the TK bond breaks, releasing CsA and SS-31. The CTS micelles demonstrated enhanced mitochondrial targeting ability and alleviated neuronal mitochondrial dysfunction and neuroinflammation in 5×FAD mice by restoring mitochondrial function and increasing anti-inflammatory cytokines.

Figure 2 CTS micelle-based mitochondria-targeted nanosystems for AD. (A) Schematic illustration of the construction, targeting, and therapeutic mechanisms of CTS micelles for AD treatment. (B) Responsive release profile of CsA from CTS micelles. (C) Intracellular mitochondrial superoxide levels and (D) mitochondrial membrane potential following various treatments in Aβ1-42-damaged primary mouse neurons. Cellular uptake of FITC-labeled CTS (FITC@CTS) in both normal and Aβ1-42-damaged (E) BV2 or (F) SH-SY5Y cells as analyzed by flow cytometry. Confocal laser scanning microscopy (CLSM) images showing the colocalization of FITC@CTS with mitochondria in (G) BV2 or (H) SH-SY5Y cells. Reproduced with permission.98 Copyright 2024, Wiley-VCH.

Furthermore, mitochondrial targeted fluorescence probe (Mito-DDP) was also designed by Li et al.¹⁵⁴ The results of confocal images have demonstrated that Mito-DDP could effectively penetrate the membrane and target to mitochondria. Besides, this probe has the effect of viscosity sensing, including mitochondrial malfunction, cellular inflammation and AD models, providing a novel strategy for exploring the pathological role of viscosity in AD.

PD

PD, the second most common neurodegenerative disorder after AD, involves dopaminergic neuron degeneration and α-synuclein (α-syn) aggregation.¹⁶¹ Mitochondrial dysfunction drives pathogenesis through impaired mitophagy and ROS overproduction.¹⁹² Critically, α-syn accumulation induces cardiolipin exposure on the OMM, disrupting respiratory chain complexes, while mtROS promote α-syn oligomerization, forming a self-amplifying pathological loop.¹⁹³

Based on the promising mitochondria-targeting properties of the TPP peptide in AD therapy, several studies have explored its use for PD treatment due to its efficient targeting capability. For example, Zhang et al constructed ursodeoxycholic acid (UDCA)-loaded macrophage-derived nanovesicles (NVs) modified with TPP (UDCA-NVs-TPP) to combat PD.¹⁵⁷ UDCA-NVs-TPP could efficiently target damaged neuronal mitochondria and restore mitochondrial dysfunction by mitigating oxidative stress, providing a promising therapeutic strategy for PD treatment. Additionally, TPP was utilized to confer mitochondria-targeting properties to an iron (Fe)-isolated single-atom nanozyme (Fe-ISAzyme) liposome (Mito@Fe-ISAzyme, MFeI).¹⁶² Cells treated with MFeI showed higher enrichment in mitochondria compared to Fe-ISAzyme, increasing mitochondrial numbers and improving therapeutic outcomes. Furthermore, sequence-targeted nanodots (TPP-rHuHF-LYC) were created by loading lycopene into recombinant human H-ferritin (rHuHF) and coupling it with TPP as the mitochondria-targeting peptide.¹⁵⁸ TPP-rHuHF-LYC efficiently targeted neuronal mitochondria via receptor-mediated transcytosis at the BBB facilitated by rHuHF and the mitochondria-targeting ability of TPP. Results indicated that TPP-rHuHF-LYC could repair mitochondrial function by enhancing mitophagy and alleviate pathological deterioration, significantly improving the therapeutic efficiency for PD. Similarly, Zheng et al designed ultrasmall Cu_2-xSe nanoparticles carrying curcumin, encapsulated within DSPE-PEG₂₀₀₀-TPP-modified macrophage membranes (CSCCT NPs).¹⁵⁹ With focused ultrasound assistance and the targeting role of TPP, CSCCT NPs specifically targeted the mitochondria of inflammatory neurons, effectively scavenging mitochondrial ROS and promoting mitochondrial biogenesis, demonstrating a promising PD therapy strategy. Moreover, nanosystems without mitochondria-targeting peptide modifications have also shown effective mitochondrial targeting. Single-atom catalysts Pt/CeO₂ were developed for PD treatment by inducing autophagy.¹⁶⁰ After 4 h of Pt/CeO₂ treatment, mitochondria in mouse midbrain dopaminergic neuronal cells (MN9D) exhibited the highest colocalization coefficient with the nanomaterials, displaying a time-dependent increase. Interestingly, this colocalization decreased significantly from 0.692 to 0.347 when MN9D cells were pre-incubated with carbonyl cyanide m-chlorophenylhydrazone (CCCP), which reduces mitochondrial membrane potential. These findings indicate that the mitochondria-targeting property of Pt/CeO₂ is mainly due to electrostatic attraction between the positively charged surface of Pt/CeO₂ and the negatively charged mitochondria. Furthermore, coating with a neutrophil membrane and modifying with RVG29 enabled RVG29@AHM@Pt/CeO₂ to cross the BBB effectively, break down mitochondrial ROS, and induce mitophagy for PD treatment, as well as improve the locomotor ability of PD mice (Figure 3).

Figure 3 RVG29@AHM@Pt/CeO2-based mitochondria-targeted nanosystems for PD. (A) Schematic illustration of the construction, targeting, and therapeutic mechanisms of RVG29@AHM@Pt/CeO2 for PD treatment. (B) TEM image of cells after Pt/CeO2 coincubation for 4 h. (C) Mechanism of Pt/CeO2 targeting of mitochondria. (D) Mitochondria colocalization images of Pt/CeO2 cultured with MN9D cells for 0, 1, 2 and 4 h. (E) ROS levels of cells. (F) Fluorescent images of the head of PD mice. (G) Latency to fall during the rotarod test of mice. (H) Delayed time to climb down during the pole test. Reproduced with permission.160 Copyright 2023, American Chemical Society.

In summary, mitochondria-targeted nanosystems represent promising strategies for treating neurodegenerative diseases through either mitochondria-targeting peptide modifications or the positive surface charge of nanosystems. Although positively charged nanosystems facilitate cellular uptake and permeability, their cytotoxicity and short blood circulation times must be considered.^194,195 Further efforts should focus on enhancing the targeting capabilities and therapeutic outcomes of these nanosystems.

Brain Tumor

Due to the critical role of mitochondria in energy supply, cell differentiation, and growth, numerous therapeutic approaches have been designed to target mitochondria for precise tumor treatment by inducing mitochondrial dysfunction, such as decreasing ATP level, disrupting redox balance, depolarizing the mitochondrial membrane potential, interfering with ion homeostasis, and dysregulating mitophagy.¹⁴² Hence, developing mitochondria-targeted nanosystems represents an effective strategy for cancer treatment by causing intrinsic apoptotic cell death.¹⁹⁶ Glioma, especially glioblastoma multiforme (GBM), is a malignant brain tumor characterized by rapid proliferation, high recurrence rates, and high mortality. Recently, mitochondria-targeted nanosystems have also been developed for the treatment of glioma or GBM, which can be achieved through mitochondria-targeted peptides or modifications of the mitochondrial cell membrane, as well as charge conversion.

Similar to their use in neurodegenerative diseases, TPP and SS-31 are commonly employed to endow nanosystems with mitochondria-targeting capabilities for brain tumor treatment. For instance, Kang et al constructed mitochondria-targeted photosensitizer-loaded albumin nanoparticles by conjugating (4-carboxy-butyl)-TPP with pheophorbide-a (PS@chol-BSA NPs) for targeting mitochondria in the treatment of malignant brain tumors.¹⁶³ TPP has also been linked to the photosensitizer Chlorin e6 (Ce6), self-assembled with drugs and ions, or encapsulated into brain endothelial cell-derived extracellular vesicles for enhanced brain penetration and mitochondria targeting, ultimately inducing mitochondrial impairment.^164,171 In addition, researchers have constructed nanosystems modified with mitochondria-targeted peptides for glioma/GBM treatment. Cascade-targeted liposomes (Lip-TPGS) were developed using glucose and TPP as targeting peptides.¹⁶⁵ Similarly, SS-31 was used to modify doxorubicin-loaded liposomes (LS-DOX) for BBB penetration and mitochondria targeting.⁴⁹

As natural biomaterials, biomimetic nanomaterials based on nanovesicles and cell membranes have emerged as promising platforms for treating brain disorders due to their excellent biocompatibility and homologous-targeting ability.^197,198 Shi et al utilized GBM-cell membranes to camouflage nanoparticles for targeting homologous cancer cells, achieving remarkable targeting efficiency and anti-GBM efficacy.¹⁹⁹ Based on the unique advantages of GBM-cell membranes, Shi et al further developed a cancer cell-mitochondria hybrid membrane strategy for GBM treatment (Figure 4).⁵⁹ Compared to single cancer cell membranes, subcellular organelle-derived membranes can enhance the immune evasion capability of nanomaterials and be tailored for specific subcellular targeting. The results showed that hybrid membrane nanosystems (HM-NPs) had the highest overlap with mitochondria, indicating their superior mitochondria-targeting properties. After hybrid membrane coating, Gboxin could be effectively delivered to the mitochondria of cancer cells, interrupting ATP synthase function, leading to electron transport and energy metabolism disruption, ultimately causing mitochondria-mediated apoptosis.

Figure 4 HM-NPs@G-based mitochondria-targeted nanosystems for brain tumor. (A) Schematic illustration of the preparation of HM-NPs@G. (B) CLSM images and (C) colocalization analysis of U87 cells after various nanosystems incubation. (D) ATP content of U87 cells after various treatments. (E) The fluorescence intensity of JC-1 monomer of U87 cells. (F) Schematic illustration of the changes of JC-1 structures with MMP. (G) TEM images of mitochondria after various treatments. (H) in vivo fluorescence images of U87-tumor bearing mice after Cy5-labeled nanosystems injection. (I) Ex vivo fluorescence images of Cy5 in major organs and brains, and the colocalization with mitochondria in GBM sites. (J) The Gboxin accumulation in major organs, tumors and brains. Reproduced with permission.59 Copyright 2023, Springer Nature.

Tumor microenvironment-triggered charge-convertible nanosystems have also been designed to enhance mitochondria uptake while reducing toxicity to normal cells. Jin et al reported pH-triggered charge-convertible micelles (GPTD) for glioma therapy.¹⁶⁶ By conjugating 2,3-dimethylmaleic anhydride to TPP-modified chitosan-poly (lactic-co-glycolic acid) polymers to form dimethyl maleic amides, these compounds convert from cationic to anionic via the transformation of amino groups to carboxyl groups in acidic microenvironments. Under the low pH conditions found in tumors, GPTD could efficiently accumulate in mitochondria following charge-mediated cellular internalization, subsequently releasing drugs to increase the anti-tumor effect. Additionally, Xiang et al designed a mitochondrion-disturbing nanosystem (GBEPPT) capable of enzyme-mediated charge conversion.¹⁶⁷ Once delivered to the tumor site where γ-glutamyl transpeptidase (GGT) is overexpressed, GBEPPT would reverse its surface charge from negative to positive. With the assistance of this positive charge, GBEPPT could easily target mitochondria to disrupt their homeostasis, resulting in enhanced deep penetration within GBM treatments.

Furthermore, some mitochondria-targeting molecules without additional targeting equipment, such as hypericin, pheophorbide a-quinolinium conjugate (PQC), and carbon dots modified with metformin and gallic acid (MGA-CDs), inherently localize to the mitochondria to trigger oxidative stress, induce severe mitochondrial dysfunction, or promote ferroptosis for GBM.^168,172,173 Recently, a novel mitochondria-targeting strategy was demonstrated by Gao et al.¹⁶⁹ They found that tertiary amine modification could confer triterpene nanoparticles (eg, oleanolic acid, lupeol, and glycyrrhetinic acid) with mitochondria-targeting properties, enabling effective GBM treatment through pyroptosis after interaction with the translocase of the outer mitochondrial membrane 70 (TOM70).

Collectively, mitochondria-targeting strategies represent a promising avenue for brain tumor treatment by generating excessive ROS, triggering oxidative stress, and exacerbating mitochondrial dysfunction. Through the use of mitochondria-targeted peptides or membrane modifications, microenvironment-responsive charge conversion, and leveraging their inherent natural properties, nanosystems can effectively target the mitochondria of tumor cells and exert their functions therein.

Ischemic Stroke

Ischemic stroke has become a prevalent neurological disorder globally, characterized by high mortality and disability rates. Following ischemic injury, mitochondrial function is compromised under hypoxic or ischemic conditions, leading to oxidative stress, microglial activation, inflammation, and ultimately neuronal cell death.²⁰⁰ Targeting mitochondria can directly modulate cellular metabolism, thereby maximizing therapeutic outcomes while minimizing toxicity. The overproduction of ROS by damaged mitochondria plays a critical role in ischemic stroke injury. Therefore, strategies aimed at targeting mitochondria represent promising approaches for mitigating ischemic stroke damage.

Similar to neurodegenerative diseases and brain tumors, TPP and SS-31 are common mitochondria-targeted modification strategies used in ischemic stroke.^50,107 For instance, Wang et al proposed a stepwise targeting nanoplatform by modified pH-responsive micelles with cRGD and TPP peptide (cRGD/TPP@Res) for brain-mitochondria targeting.¹⁷⁴ Upon entering ischemic tissues with an acidic environment, the PEG shell detaches from the micelles due to the breakage of acetal bonds, followed by exposing TPP for mitochondria targeting. Resveratrol accumulates within the mitochondria, effectively scavenging ROS and alleviating oxidative stress and inflammation.

Ceria nanoenzymes (CeNZs) have garnered attention due to their excellent ROS scavenging capabilities and reversible conversion properties.^201,202 Liao et al developed a mitochondria-targeted nanosystem based on CeNZs and incorporated roflumilast for synergistic treatment of ischemic stroke (Figure 5A–5D).¹⁷⁵ After TPP-targeted modification, TPP@(CeO₂+ROF) nanosystems were rapidly taken up by neuronal cells within 1.5 h, exhibiting higher co-localization with mitochondria compared to non-targeting nanosystems. Additionally, TPP@(CeO₂+ROF) exhibited effective ROS scavenging, mitochondrial function regulation, and anti-inflammatory properties, demonstrating comprehensive treatment of ischemic stroke. To improve the brain-targeting ability of nanosystems, they further developed a magnetic field-driven and mitochondria-targeting ceria nanosystem (MMTCe) by anchoring TPP-Ce nanoparticles coated with BV2 cell membranes to maleimide-functionalized superparamagnetic iron oxide nanoparticles (Figure 5E–5H).¹⁷⁶ Under external magnetic field guidance, MMTCe efficiently reached the brain and targeted damaged mitochondria with the assistance of TPP. Subsequently, MMTCe exerted its therapeutic efficiency by scavenging ROS, reducing oxidative stress, thereby rebalancing the ischemic microenvironment. This study presented a magnetically driven, mitochondria-targeted nanosystem, providing a multifaceted approach for ischemic stroke treatment.

Figure 5 Ce-based mitochondria-targeted nanosystems for ischemic stroke. (A) Schematic illustration of the construction, mitochondria-targeting, and therapeutic effects of TPP@(CeO2+ROF). (B) Co-localization of nanosystems with mitochondria in PC12 cells. (C) TEM images of TPP@(CeO2+ROF) in mitochondria of PC12 cells. (D) JC-1 fluorescence analyzed by flow cytometry. Reproduced with permission.175 Copyright 2024, American Chemical Society. (E) Schematic representation of the preparation of MMTCe nanosystems and their neuroprotective effects. (F) CLSM images of mitochondria-targeted ability of DiR-labeled MMCe and MMTCe. (G) Ex vivo fluorescence images of brain and section from rats after various treatments. (H) The cerebral infarct volume using TTC staining. Reproduced with permission.176 Copyright 2025, Wiley-VCH.

Mitochondrial dysfunction plays a significant role in the pathogenesis of ischemic stroke, impairing energy supply, exacerbating oxidative stress, and causing neuronal death. Hence, restoring mitochondrial functions is essential in treating ischemic stroke. Researchers have recently employed mitochondria-targeted peptides, including TPP and SS-31, to modify nanosystems for scavenging ROS, alleviating inflammation, and promoting mitophagy. Further investigations should focus on mitochondrial biology and specific molecular mechanisms, which will facilitate the development of novel mitochondria-targeted approaches in ischemic stroke treatment.

Others

Similar to acute central nervous system injuries and neurodegenerative diseases, mitochondrial dysfunction also plays an essential role in other brain disorders, such as traumatic brain injury (TBI), cognitive deficits, and neuropathy.^203,204 Neurological functions are impaired by changes in mitochondria resulting from increased ROS production and decreased energy supply. Therefore, proposing potential therapeutic approaches for reversing mitochondrial dysfunction is crucial for the treatment of brain diseases.

TBI is a complex and biphasic condition. The initial phase involves direct tissue damage, while the secondary phase is characterized by calcium overload, excessive ROS production, and inflammation.²⁰⁵ Mitochondrial dysfunction frequently occurs during this secondary phase. Consequently, mitochondria represent a promising target for intervention in TBI. Researchers have developed mitochondria-targeted nanosystems for managing TBI. For instance, Sharma et al utilized polyamidoamine dendrimers to encapsulate N-acetyl cysteine (NAC), which acts as an antioxidant.¹⁷⁷ After being modified with TPP, the NAC was specifically targeted to the mitochondria in injured glial cells. This approach significantly reduced oxidative stress both in vitro using cell models and in vivo using rabbit TBI models, demonstrating that mitochondria-targeted strategies could enhance therapeutic efficacy in TBI.

Furthermore, Sun et al introduced a biomimetic nanosystem co-modified with C3 peptides and SS31 (C3/SS31-RBCNLCs) for targeting neuronal mitochondria in the brain.¹⁷⁸ Both in vitro and in vivo experiments showed that the encapsulated drug olaparib could be efficiently delivered into brain mitochondria, thereby improving mitochondrial function, reducing neuronal death, and delaying the pathological progression of TBI. Besides, various fluorescence probes were also constructed by researchers to realize mitochondria-targeting and brain imaging. For instance, Pan et al proposed a ligand engineering of luminescent AuAg nanoclusters conjugated with TPP on the surface.¹⁷⁹ In vitro cell experiments have revealed that AuAg NCs@TPP probe could effectively target to the mitochondria of 4T1 and BV2 cells, exhibiting outstanding mitochondria-targeted property.

Conclusion and Perspective

Mitochondria, as central orchestrators of cellular energetics, calcium homeostasis, and apoptotic signaling, represent pivotal therapeutic targets for CNS disorders. Mounting evidence implicates mitochondrial dysfunction as a convergent pathological mechanism underpinning neurodegenerative diseases (eg, AD, PD), brain tumors, ischemic stroke, and TBI. Consequently, strategies aimed at restoring mitochondrial homeostasis hold transformative potential for CNS therapeutics. Mitochondria-targeted nanosystems have emerged as a paradigm-shifting approach, enabling spatiotemporally precise delivery of therapeutic cargo to rescue mitochondrial function and amplify treatment efficacy.

This review has delineated the rational design principles and expanding therapeutic applications of mitochondria-targeted nanosystems. Key targeting modalities—including cationic molecules, mitochondrial-penetrating peptides, and bioengineered mitochondrial membranes—demonstrate markedly enhanced mitochondrial accumulation and intervention capacity. We further synthesized recent advances in deploying these nanosystems across diverse CNS pathologies (including AD, PD, glioma, ischemic stroke, and TBI etc)., highlighting their roles in mitigating oxidative stress, modulating mitophagy, and promoting mitochondrial biogenesis to achieve superior therapeutic outcomes. Despite these promising advances, critical challenges demand resolution before clinical translation (Figure 6).

Figure 6 Current challenges and future prospects of mitochondria-targeted nanosystems. Created with BioRender.com.

To date, mitochondria-targeted nanosystems have yet to be employed in clinical studies, potentially due to challenges related to their complex preparation, reproducibility, and metabolism. Consequently, greater emphasis should be placed on the thorough investigation of the physicochemical characterization of these nanosystems. Moreover, before these systems can advance to preclinical trials, it is essential to evaluate their in vivo stability, long-term effects, and metabolic pathways. Addressing these aspects will be crucial for translating mitochondria-targeted nanosystems from experimental models to potential clinical applications.

Size, shape, and charge play essential roles in determining the biological fate of nanosystems, which influence their in vivo cellular uptake and circulation lifetime.^206,207 For example, nanosystems with over 200 nm size have poor penetration and cell interaction properties. In contrast, nanosystems with small size can enhance the penetration, but are rapidly cleared from the systems by kidneys during the in vivo circulation.²⁰⁸ As for the charge of nanosystems, the cationic charge of nanosystems improves cellular uptake efficiency, which is mainly attributed to the negative charge of cell membrane, but it is also associated with cytotoxicity. For instance, the inherent cationic charge of common mitochondrial ligands (eg, TPP) raises concerns regarding membrane perturbation and off-target cytotoxicity. Hence, future research must prioritize rigorous toxicological profiling of nanosystems across relevant cell types and disease models, coupled with the development of less cytotoxic strategies such as coating with biomimetic mitochondrial membranes and engineering delivery systems with targeted ligands.

Effective CNS delivery necessitates sequential navigation of formidable obstacles: the BBB, the complex brain parenchyma, and ultimately, the mitochondrial double membranes. Furthermore, in order to enhance the accumulation of nanosystems in the mitochondria of specific cell types, various sub-organelle targeting strategies have been developed in combination with mitochondria-targeted approaches. For instance, T807 and TPP peptides were co-functionalized to red blood cell-modified nanosystems by Gao et al, which could not only penetrate the BBB but also target neuronal mitochondria.¹⁴⁹ The similar functions could also be observed by RVG29 peptide modification.¹⁵² While dual-targeting strategies (eg, conjugating BBB-penetrating ligands like transferrin or angiopep-2 with mitochondrial homing signals like SS-31) show promise, their efficiency remains limited. A concerted effort is required to engineer next-generation ligands with enhanced specificity, avidity, and stimuli-responsiveness for both brain entry and mitochondrial localization, thereby minimizing systemic exposure and maximizing the therapeutic index.

A fundamental limitation of current platforms is their inability to distinguish pathologically damaged mitochondria from functional counterparts. Cellular homeostasis relies on mitochondrial quality control mechanisms: damaged organelles (exhibiting fragmentation, depolarized membrane potential, and proteotoxic/oxidative stress) are segregated via fission and targeted for mitophagy, while healthy units sustain essential functions. Indiscriminate nanocarrier accumulation in all mitochondria poses potential risks. Delivery of cytotoxic payloads or nanomaterial-induced stress to healthy mitochondria could irreversibly compromise cellular viability. Next-generation systems demand molecular intelligence for damaged mitochondrial targeting, such as energy-state-responsive delivery, damage marker-guided binding, or ROS/protease-activatable systems.

In summary, subcellular targeting strategies, including but not limited to mitochondrial-targeted nanosystems, offer promising approaches for treating CNS diseases. Future success hinges on prioritizing safety by design, enhancing targeting sophistication, and demonstrating scalable manufacturability, paving the way for these potent nanoscale interventions to transform the treatment landscape for devastating neurological diseases.

Data Sharing Statement

No data was used for the research described in the article.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Conceptualization: Y.Z., X.C. and X.Z.; literature curation: X.Z., J.C. and B.W., writing – original draft: X.Z., J.C., B.W. and X.C.; writing—review and editing: Y.Z. and X.C.; supervision: Y.Z. All authors read and approved the final manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82473900, 82273903), Zhejiang Provincial Natural Science Foundation (LD25H090002), and Research Project of Zhejiang Chinese Medical University (2025JKZKTS33).

Disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

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