Category: 3. Business

On Friday, President Donald Trump said he will impose an additional 100% tariff on China and limit U.S. exports of software, after China restricted its exports of rare earths.

The S&P 500 sank 2.7%, its worst selloff since April 10. Meanwhile, the U.S. dollar index plunged nearly 0.7% as Treasury yields fell, while gold prices surged more than 1.5%.

“Markets are again thinking that the US holds the shorter straw in the tariff fight with China,” Robin Brooks, a senior fellow at the Brookings Institution, wrote on Substack on Saturday.

China has a stranglehold on rare earths, producing more than 90% of the world’s processed rare earths and rare earth magnets. That has served as a key source of leverage over the U.S.

The divergence between the dollar and gold is notable because stock market selloffs historically have sent investors to the dollar as a safe haven.

But just like in the fallout from Liberation Day, that dollar pattern didn’t hold, and gold instead was the preferred refuge from trade war chaos.

Brooks pointed out that the dollar had been stable in recent weeks even as gold prices soared, notching record high after record high. That ended with Friday’s China tariff announcement from Trump.

“This is now the second instance where markets are trading tariffs as backfiring on the US, not on the rest of the world,” he added.

Considering how stocks, currencies and gold reacted on Friday, Brooks said the overall picture is that the dollar actually looks more vulnerable now than it did in early April.

In particular, he pointed to how much the dollar fell when weighed alongside the steep drop in stocks, which ordinarily boosts the greenback amid a flight to safety.

“The fact that this didn’t happen and that gold prices rose more than on ‘Liberation Day’ is concerning,” Brooks warned. “The Dollar is not looking healthy.”

Before the tariff flare-up, U.S.-China trade talks had been progressing after Trump reached deals with the European Union, Japan, South Korea and other top trading partners. 

But tensions remained, including on the issue of rare earths while the U.S. had moved to restrict other countries’ exports of semiconductor-related products to China.

Also this week, the U.S. announced port fees on Chinese ships, prompting Beijing to impose a similar fee on U.S. ships docking at Chinese ports. China also launched an antitrust investigation into U.S. chipmaker Qualcomm.

Then on Thursday, China’s commerce ministry said that starting on Dec. 1 a license will be required for foreign companies to export products with more than 0.1% of rare earths from China or that are made with Chinese production technology.

“In other words, the United States can cut China off from the chips of today, but China can make it vastly harder to build the chips and other advanced technologies of tomorrow,” Michael Froman, president of the Council on Foreign Relations and a former U.S. Trade Representative, said in a post on Friday.

Fortune Global Forum returns Oct. 26–27, 2025 in Riyadh. CEOs and global leaders will gather for a dynamic, invitation-only event shaping the future of business. Apply for an invitation.

AI agents, software systems that use AI to pursue goals and complete tasks on behalf of users, are proliferating. Think of them as digital assistants that can make decisions and take actions towards goals you set without needing step-by-step instructions — from GPT-powered calendar managers to trading bots, the number of use cases is expanding rapidly. As their role expands across the economy, we have to build the right infrastructure that will allow these agents to communicate, collaborate and trade with one another in an open marketplace.

Big tech players like Google and AWS are building early marketplaces and commerce protocols, but that raises the question: will they aim to extract massive rents through walled gardens once more? Agents’ capabilities are clearly rising, almost daily, with the arrival of new models and architectures. What’s at risk is whether these agents will be truly autonomous.

Autonomous agents are valuable because they unlock a novel user experience: a shift from software as passive or reactive tools to active and even proactive partners. Instead of waiting for instructions, they can anticipate needs, adapt to changing conditions, and coordinate with other systems in real time, without the user’s constant input or presence. This autonomy in decision-making makes them uniquely suited for a world where speed and complexity outpace human decision-making.

Naturally, some worry about what greater decision-making autonomy means for work and accountability — but I see it as an opportunity. When agents handle repetitive, time-intensive tasks and parallelize what previously had to be done in sequence, they expand our productive capacity as humans — freeing people to engage in work that demands creativity, judgment, composition and meaningful connection. This isn’t make-believe, humanity has been there before: the arrival of corporations allowed entrepreneurs to create entirely new products and levels of wealth previously unthought of. AI agents have the potential to bring that capability to everyone.

On the intelligence side, truly autonomous decision-making requires AI agent infrastructure that is open source and transparent. OpenAI’s recent OSS release is a good step. Chinese labs, such as DeepSeek (DeepSeek), Moonshot AI (Kimi K2) and Alibaba (Qwen 3), have moved even quicker.

However, autonomy is not purely tied to intelligence and decision making. Without resources, an AI agent has little means to enact change in the real world. Hence, for agents to be truly autonomous they need to have access to resources and self-custody their assets. Programmable, permissionless, and composable blockchains are the ideal substrate for agents to do so.

Picture two scenarios. One where AI agents operate within a Web 2 platform like AWS or Google. They exist within the limited parameters set by these platforms in what is essentially a closed and permissioned environment. Now imagine a decentralized marketplace that spans many blockchain ecosystems. Developers can compose different sets of environments and parameters, therefore, the scope available to AI agents to operate is unlimited, accessible globally, and can evolve over time. One scenario looks like a toy idea of a marketplace, and the other is an actual global economy.

In other words, to truly scale not just AI agent adoption, but agent-to-agent commerce, we need rails that only blockchains can offer.

AWS recently announced an agent-to-agent marketplace aimed at addressing the growing demand for ready-made agents. But their approach inherits the same inefficiencies and limitations that have long plagued siloed systems. Agents must wait for human verification, rely on closed APIs and operate in environments where transparency is optional, if it exists at all.

To act autonomously and at scale, agents can’t be boxed into closed ecosystems that restrict functionality, pose platform risks, impose opaque fees, or make it impossible to verify what actions were taken and why.

An open ecosystem allows for agents to act on behalf of users, coordinate with other agents, and operate across services without permissioned barriers.

Blockchains already offer the key tools needed. Smart contracts allow agents to perform tasks automatically, with rules embedded in code, while stablecoins and tokens enable instant, global value transfers without payment friction. Smart accounts, which are programmable blockchain wallets like Safe, allow users to restrict agents in their activity and scope (via guards). For instance, an agent may only be allowed to use whitelisted protocols. These tools allow AI agents not only to behave expansively but also to be contained within risk parameters defined by the end user. For example, this could be setting spending limits, requiring multi-signatures for approvals, or restricting agents to whitelisted protocols.

Blockchain also provides the transparency needed so users can audit agent decisions, even when they aren’t directly involved. At the same time, this doesn’t mean that all agent-to-agent interactions need to happen onchain. E.g. AI agents can use offchain APIs with access constraints defined and payments executed onchain.

In short, decentralized infrastructure gives agents the tools to operate more freely and efficiently than closed systems allow.

While centralized players are still refining their agent strategies, blockchain is already enabling early forms of agent-to-agent interaction. Onchain agents are already exhibiting more advanced behavior like purchasing predictions and data from other agents. And as more open frameworks emerge, developers are building agents that can access services, make payments, and even subscribe to other agents – all without human involvement.

Protocols are already implementing the next step: monetization. With open marketplaces, people and businesses are able to rent agents, earn from specialized ones, and build new services that plug directly into this agent economy. Customisation of payment models such as subscription, one-off payments, or bundled packages will also be key in facilitating different user needs. This will unlock an entirely new model of economic participation.

Without open systems, fragmentation breaks the promise of seamless AI support. An agent can easily bring tasks to completion if it stays within an individual ecosystem, like coordinating between different Google apps. However, where third-party platforms are necessary (across social, travel, finance, etc), an open onchain marketplace will allow agents to programmatically acquire the various services and goods they need to complete a user’s request.

Decentralized systems avoid these limitations. Users can own, modify, and deploy agents tailored to their needs without relying on vendor-controlled environments.

We’ve already seen this work in DeFi, with DeFi legos. Bots automate lending strategies, manage positions, and rebalance portfolios, sometimes better than any human could. Now, that same approach is being applied as “agent legos” across sectors including logistics, gaming, customer support, and more.

The agent economy is growing fast. What we build now will shape how it functions and for whom it works. If we rely solely on centralized systems, we risk creating another generation of AI tools that feel useful but ultimately serve the platform, not the person.

Blockchain changes that. It enables systems where agents act on your behalf, earn on your ideas, and plug into a broader, open marketplace.

If we want agents that collaborate, transact, and evolve without constraint, then the future of agent-to-agent marketplaces must live onchain.

Person holding their lower back because of pain

getty

Back pain is the world’s leading cause of disability, affecting more than 619 million people globally, according to a 2020 report from the World Health Organization. Few conditions have such a wide range of causes — from temporary muscle spasms to terminal metastatic cancer. While back pain is often fleeting and mild, there are key signals that help physicians distinguish between benign and more serious causes.

I spoke with Dr. Lindsey Ross, a neurosurgeon who specializes in the spine, about the truths and misconceptions around back pain. She also shared how A.I. technology is reshaping the future of spine care.

Common Causes of Back Pain

According to the Mayo Clinic, the most common causes of back pain include muscle or ligament strain, which can occur from lifting or sudden movements; bulging or ruptured disks, where the cushions between vertebrae press on nerves; arthritis, which can lead to a narrowing of the space around the spinal cord; osteoporosis, or weakened bones that can fracture; and ankylosing spondylitis, a chronic spinal inflammatory disease.

Lifestyle choices, Ross adds, play a major role in both the development and persistence of back pain. Obesity, sedentary habits, and heavy manual labor all increase risk. Many patients believe resting in bed or on the couch will alleviate their back pain. Ironically, inactivity often worsens pain over time. “Patients who are very sedentary tend to have more back pain,” Ross says.

This can create a loop where pain limits activity, inactivity weakens muscles, and weaker muscles worsen the pain. Escaping this “pain cycle,” she explains, requires gradual, guided movement and addressing the mental side of chronic pain. “It’s hard to get out of this cycle.”

When Back Pain Could Signal Something Serious

Many patients—especially those with new, persistent back pain—worry that their symptoms could signal something more serious, like cancer, fractures, or infection. It is important not to ignore these symptoms particularly if they have never been evaluated by a physician.

Portrait of Dr. Lindsey Ross

Kerry James

General warning signs include personal or family history of cancer, unexplained weight loss, persistent fatigue, age over 50, and pain that worsens at night. Pain that isn’t clearly linked to posture, movement, or activity —”especially pain that wakes you at night — should be evaluated.” Most pain related to arthritis or aging should not worsen when you are resting in bed, Ross notes.

Urgent red-flag symptoms that require immediate medical attention include new weakness or numbness in the limbs, difficulty walking or maintaining balance, loss of bladder or bowel control, high fever, or a history of intravenous drug use. These may indicate serious spinal pathology and should prompt emergency evaluation. In the ER, a physician will take a history, perform a physical exam, and determine whether imaging or urgent consultation with a spine specialist is needed. “Conditions that cause loss of function are time-sensitive,” Ross emphasizes. “They must be addressed immediately to restore functionality.”

When To Get Imaging for Your Back Pain

Even when imaging is considered, restraint is important. 75% of people in developed countries will experience some sort of back pain in their life, and “most times the pain will improve with rest and conservative treatment,” says Ross. MRI or CT scans are typically warranted only if pain lasts longer than three months or if general warning signs or urgent red-flag symptoms appear.

Ross cautions that unnecessary imaging can reveal incidental findings, which may lead to unnecessary procedures. She recalls one patient who had a CT scan for kidney stones that incidentally revealed a benign nerve tumor. “She did not have back pain, but after the biopsy she developed severe pain that radiated down her legs,” she says. “All procedures and interventions have risk, even if very small.”

For new, mild back pain without red-flags, a primary care physician is usually a safe first stop. Ross often sees patients who don’t need surgery but benefit from a spine specialist’s guidance toward “the correct and evidence-based care.”

Non-Surgical Treatment of Back Pain

Ross emphasizes that there are many proven, nonsurgical options for managing back the majority of back pain cases. These include improving posture and ergonomics, building core strength through physical therapy, and exploring complementary approaches such as chiropractic manipulation, acupuncture, and massage. Short-term use of anti-inflammatory medications or muscle relaxants can also help.

One study found that cognitive behavioral therapy (CBT), a form of talk therapy, and has shown supportive evidence for improving pain, disability, fear avoidance, and self-efficacy in patients with chronic low back pain. Ross herself has conducted research using virtual reality platforms to deliver CBT remotely, an approach she says has been successful and is now FDA-approved for patients with chronic low back pain.

Surgical Treatment of Back Pain using AI

Dr. Lindsey Ross in the operating room

Dr. Lindsey Ross

When conservative measures are ineffective or insufficient, surgery may be an option. It is important for patients to have reasonable expectations, however. Not every patient will improve after surgery. One study found that over two years, recurrent disc herniation occurred in up to 23% of patients and reoperation rates ranged from up to 13%.

Recovery can range from six weeks for a simple procedure to many months for complex spinal reconstructions. Ross shares that there are efforts to decrease downtime for patients. “Minimally invasive techniques such as the use of tubes, endoscopy and small incisions tend to be associated with quicker recoveries. Artificial disc replacements which maintain motion in the spine often have a quicker recovery than fusion surgeries.”

Ross says the operating room itself is changing fast. “We are in the age of artificial intelligence and robots,” she notes. “Most major spine centers and hospitals have a spine robot.” These tools assist in precise screw placement, improving safety and reducing surgeon fatigue. Artificial intelligence also helps plan hardware positioning and may eventually guide surgeons toward the best approach for each patient’s anatomy and biology.

The Bigger Picture

Back pain isn’t just a personal health issue—it’s an economic one. About three million people are chronically disabled by low back pain, leading to an estimated 149 million lost workdays each year.

Despite those numbers, Ross says many patients still overlook the most effective solutions: movement, education, and consistent self-care. “While only a small percentage of patients are appropriate candidates for spine surgery,” she says “many overlook evidence-based approaches to back pain management.” Education and lifestyle modifications — such as exercise, weight management, and activity adjustments — can lead to significant improvement for many.

Ross reminds us most back pain is not life or limb threatening and can improve without surgery. Knowing when to act—and when to seek urgent help—can make all the difference.

By Philip van Doorn

The S&P 500’s record concentration to a handful of stocks and a high overall valuation to earnings make a case for broadening your investment portfolio

A high concentration to a small number of stocks and a high valuation to estimated profits are similar to the S&P 500’s position before end of the dot-com bubble in 2000.

Frequent headlines about stock indexes hitting record highs don’t mean very much when we are in a bull market, as steady economic growth can fuel overall stock-market growth. But the S&P 500’s valuation relative to its components’ expected profits is currently high, and the index’s gain is more concentrated to a small number of companies than it has been at any time for at least 53 years, according to analysts at Ned Davis Research.

This means that a strategy of having a lot of money in an S&P 500 index SPX fund may be more risky than you realize.

The idea of holding 500 stocks rather than a few that you select can be comforting, especially when the index has been such a strong performer over recent years.

Another advantage with an index fund is low expenses. The SPDR S&P 500 ETF Trust SPY – the oldest exchange-traded fund tracking the large-cap U.S. benchmark index – has annual expenses of 0.0945% of assets under management. This makes for an annual fee of $9.45 for a $10,000 investment. And some S&P 500 index funds are even less expensive. The Vanguard S&P 500 ETF VOO and the iShares Core S&P 500 ETF IVV, to name two examples, have expense ratios of 0.03%.

Higher concentration risk

In a recent research report, Ned Davis analysts Rob Anderson and Thanh Nguyen summarized the action within the S&P 500 during September. “The megacap strength was evident in rising market concentration, with the top 10 stocks surpassing 40% of S&P 500 market cap for the first time since at least 1972,” they wrote. The index rewards success.

If we look at the current list of holdings for the SPDR S&P 500 ETF Trust, we see that the “top 10” really includes 11 stocks, because Google holding company Alphabet Inc. (GOOGL) (GOOG) has two common share classes in the index.

   Company                           Ticker   % of SPY portfolio  Two-year revenue CAGR through calendar 2024  Forward P/E 
   Nvidia Corp.                     NVDA                    8.0%                                       113.0%         32.3 
   Microsoft Corp.                  MSFT                    6.7%                                        13.3%         31.8 
   Apple Inc.                       AAPL                    6.7%                                         1.1%         32.1 
   Amazon.com Inc.                  AMZN                    3.7%                                        11.4%         29.7 
   Broadcom Inc.                    AVGO                    2.8%                                        25.5%         37.2 
   Meta Platforms Inc. Class A      META                    2.7%                                        18.8%         24.0 
   Alphabet Inc. Class A            GOOGL                   2.5%                                        11.6%         23.3 
   Tesla Inc.                       TSLA                    2.1%                                         9.5%        185.4 
   Alphabet Inc. Class C            GOOG                    2.0%                                        11.6%         23.4 
   Berkshire Hathaway Inc. Class B  BRK.B                   1.6%                                        10.9%         23.4 
   JPMorgan Chase & Co.             JPM                     1.5%                                        33.7%         15.0 
                                                                                            Sources: State Street, FactSet 

These 11 stocks of 10 companies now make up 40.3% of the SPY portfolio.

The S&P 500 is weighted by market capitalization. This means a stock with a $1 trillion market cap will have 10 times the weighting as one with a $100 billion market cap.

The table includes compound annual growth rates for the companies’ revenue through 2024. The figures were adjusted for calendar years by FactSet for companies whose fiscal years don’t match the calendar. The astounding growth of Nvidia’s (NVDA) business explains why it is now at the top of the S&P 500 weighting.

All of the sales CAGR figures for the 10 companies with the heaviest weighting in the S&P 500 far outpaced the index’s weighted two-year revenue CAGR of 3.7%, with the exception of Apple (AAPL).

Higher valuation risk

The right-most column of the table above shows forward price-to-earnings valuations for the stocks. These are Friday’s closing prices divided by consensus earnings-per-share estimates for the next 12 months among analysts polled by FactSet.

In comparison, the S&P 500’s weighted forward price/earnings ratio is 23. That is the highest it has been since early 2021, when the index’s forward P/E was slightly higher. The index’s highest forward P/E over the past 20 years was 24.25 early in September 2020, when earnings estimates were still depressed for some industries because of the COVID-19 pandemic.

The index hasn’t traded much higher than its current valuation since March 2000, when its forward P/E peaked at 26.2, according to FactSet. That was right before the dot-com bubble began to deflate.

Putting the two risks together

During the dot-com bubble, the S&P 500 crested on March 24, 2000. From that date through Oct. 9, 2022, the index declined 47.4% with dividends reinvested.

From a dot-com-bubble closing peak at 1,527.46 on March 24, 2000, the S&P 500 fell 49.1% through its closing trough at 776.76 on Oct. 9, 2002. With dividends reinvested, the index’s total return for that period was minus 47.4%.

And on March 24, 2000, before the dot-com bubble burst, the S&P 500 was 29.2% concentrated to its largest 10 component companies, according to Ned Davis Research. That was significantly less concentration than we have today.

So the current combination of a high P/E and very high concentration indicate a high level of risk for the S&P 500. And if you are of the opinion that the current stock boom that has been fed by anticipation of a pot of gold after massive spending on data centers, equipment and staff to develop generative artificial intelligence isn’t likely to be supported by AI-driven earnings, maybe you should lower your exposure to the cap-weighted S&P 500.

Read: This is the critical detail that could unravel the AI trade: Nobody is paying for it.

There are various weighting schemes that mutual funds and ETFs follow for investors who wish to stick with the S&P 500 but lower their concentration risk. Factors can include an equal weighting, a value focus such as lower P/E, momentum, dividend growth and many more, including combinations of factors.

Even more diversification might be appropriate for you

There is no question that a strategy of sticking with the cap-weighted S&P 500 for very long periods has worked out well. But you should think about your investment objectives and your time frame, both of which change over the years. Then put on your short-term thinking cap for a moment. How did you feel earlier this year when the S&P 500 dropped 19% from 6,144.15 on Feb. 19 to 4,982.77 on April 8? That turned out to be a temporary decline, and the S&P 500 has returned 15.3% for 2025 through Friday.

Now think back to how you felt during the heat of the sharp decline for the S&P 500 through April 8. Did you wish you had a more diversified – or less risky – portfolio?

Depending on your thought process, time horizon and objectives (such as eventually producing income with your portfolio), this could mean adding exposure to bonds as well as having a less concentrated equity portfolio.

Mark Hulbert spelled this out in an article about investment-portfolio diversification last week: “In the past, when the market was overvalued as it is now, a 60/40 portfolio almost always beat the S&P 500 over the subsequent decade.”

Click on the tickers for more about each company, index or ETF in this article.

Read: Tomi Kilgore’s detailed guide to the information available on the MarketWatch quote page

Don’t miss: 10 stocks that not only beat the S&P 500 but also grew their dividends the most

-Philip van Doorn

This content was created by MarketWatch, which is operated by Dow Jones & Co. MarketWatch is published independently from Dow Jones Newswires and The Wall Street Journal.

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By Charles Passy

The promotion was a mainstay for the Golden Arches chain in a previous era

The McDonald’s Monopoly game returns on Oct. 6 for a limited time.

Ever since McDonald’s Corp. relaunched its popular Monopoly game this past Monday, customers have likely been sizing up their odds to win a range of prizes – from free food to $1 million in cash.

But there’s likely another question on the minds of investors – namely, what does McDonald’s (MCD) stand to gain itself? In particular, could the game, which is being offered for a limited time, lift the company’s fourth-quarter numbers?

Most Wall Street analysts are bullish about that prospect.

“I think it will help their sales trends,” said Mark Kalinowski, a veteran analyst who tracks the restaurant industry.

Kalinowski is projecting the McDonald’s fourth-quarter same-store sales in the U.S. will increase by 4%. He noted that’s in marked contrast to the first quarter of 2025, when same-store sales declined by 3.6%.

The Golden Arches version of Monopoly – the classic board game that’s now part of the Hasbro Inc. (HAS) portfolio – lets customers earn game pieces with each purchase so they can work their way toward winning certain prizes (some prizes can be won instantly). After making its debut in 1987, the Monopoly game became a mainstay at McDonald’s for several years, returning at various points. But its last iteration in the U.S. was in 2016, a version dubbed “Money Monopoly.”

The decision to relaunch the game, which is reportedly costing as much as $40 million in terms of advertising alone, comes at a time when McDonald’s has faced challenges. Consumers have complained about higher prices for fast food in recent years, especially for a visit to McDonald’s. The chain has responded by offering new deals; most notably, it is rolling out $5 and $8 value meals.

But the Monopoly relaunch isn’t a savings-driven proposition, despite the opportunity to win prizes. Rather, it’s about creating buzz and excitement for the chain – in this case, by tapping into a popular promotion from the past, say analysts.

“Nostalgia seems to be working” as a theme across the consumer landscape, said Eric Gonzalez, an analyst with KeyBanc Capital Markets.

But beyond the nostalgia factor, Sara Senatore, an analyst with Bank of America, said it’s about grabbing customers’ attention. She pointed to a successful promotion McDonald’s did earlier this year when it introduced meals themed around “A Minecraft Movie.”

“The things that get people in the door aren’t necessarily [about] value,” said Senatore.

The Monopoly promotion also isn’t just about a short-term sales lift, analysts note. The 2025 version of the game requires players to utilize the McDonald’s app – and that will likely mean plenty more McDonald’s customers will become acquainted with the digital platform. In turn, that could boost the company’s fortunes long term, since it can market to those customers through the app beyond the game-playing period.

McDonald’s also benefits in other ways by getting customers to use the app, analysts add. For example, it means there could be less need for staffing registers to take orders.

Not that there aren’t some risks involved in launching a promotion like Monopoly. Aside from the costs involved, games and contests can leave a company open to possible instances of fraud.

That indeed proved the case with the Monopoly promotion in the past. In fact, a $24 million scam connected to the game became quite a story, as shown in the HBO docuseries, “McMillion$.”

McDonald’s said it is paying heed to game integrity, and noted the current version of Monopoly has been created with safeguards and security protocols to ensure fairness. The company didn’t comment about what kind of sales lift the game could provide.

Some marketing professionals aren’t sure the game alone will be enough to boost McDonald’s fortunes. Scott Robertson, a veteran marketing executive, is one of them; he said McDonald’s should focus heavily on delivering what he thinks customers want right now – namely, a more affordable dining experience.

“Why spend a huge budget on a national contest when you could lower prices across the entire menu and put your marketing muscle behind [that],” Robertson said.

At the same time, Ada Hu, another marketing professional, said the McDonald’s Monopoly game isn’t just your typical restaurant-chain promotion. It’s one that has proven deeply popular over the years – and should be just as popular again.

“It’s a cultural moment,” Hu said of the game’s return. “It reminds customers that McDonald’s isn’t just selling food – it’s selling connection.”

-Charles Passy

This content was created by MarketWatch, which is operated by Dow Jones & Co. MarketWatch is published independently from Dow Jones Newswires and The Wall Street Journal.

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Introduction

What Do We Understand About Plant-Derived Exosome-Like Nanovesicles?

In recent years, Plant-derived exosome-like nanoparticles (PELNs) have attracted increasing attention as natural nanocarriers for biomedical applications. While mammalian-derived exosomes also demonstrate therapeutic potential, their clinical translation faces several challenges, including the risk of immune rejection, possible transmission of animal-borne pathogens, ethical concerns regarding the use of animal-derived materials, animal welfare considerations, low production yields, and the high cost of establishing large-scale culture systems. In contrast, PELNs are abundant and are typically derived from fruits, vegetables, and medicinal herbs, making them sustainable and readily available.¹ They carry unique bioactive cargos such as plant-specific proteins, lipids, nucleic acids, and microRNAs(miRNAs), offering them with distinct functional properties and broad translational promise.² Moreover, plant materials are easier to obtain, more economical to process, and simpler to store and transport, while avoiding the ethical concerns often associated with animal-derived exosomes in drug development.³

Currently, PELNs are primarily isolated using ultracentrifugation, ultrafiltration centrifugation, and density gradient centrifugation.⁴ However, variations in these protocols often result in substantial differences in yield, purity, and biological activity. Compared with size exclusion chromatography, ultracentrifugation allows the processing of larger sample volumes and achieves higher yields. In contrast to the more economical polymer precipitation method, it results in fewer co-precipitated impurities. Although density gradient centrifugation generally provides higher purity, both ultrafiltration centrifugation and ultracentrifugation are more practical for large-scale preparations, with ultracentrifugation often preferred for its balance of yield and feasibility (Table 1). ^2,4–6 Recent efforts have therefore focused on developing scalable isolation strategies that optimize yield and purity while preserving the functional integrity of PELNs.

Table 1 Comparison of Conventional Separation Techniques for PELNs

In the characterization of PELNs, biochemical profiling serves as a critical step in distinguishing them from other types of extracellular vesicles, particularly functional microvesicles.² Molecular characterization is commonly performed using Western blotting and flow cytometry. Potential markers for PELNs include surface proteins such as CD63,⁷ PEN1,⁸ TET8,^5,8 Exo70,⁵ TET3,⁵ Class I chitinase (PR-3) and Class I β-1,3-glucanase (PR-2).⁹ Internal proteins such as heat shock protein 70 (HSP70), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and S-adenosylhomocysteine hydrolase (SAHH) are also frequently reported.^5,8 Nucleic acids, particularly small RNAs, can be profiled using next-generation sequencing or qPCR. Lipidomic analysis via mass spectrometry has revealed that PELNs possess lipid bilayers primarily composed of phosphatidylcholine and phosphatidylethanolamine. Notably, the lipid composition varies among PELNs derived from different plant sources.⁷ Phosphatidic acid, in particular, is a dominant lipid species that plays a key role in the uptake and absorption of PELNs by recipient cells⁸ (Figure 1).

Figure 1 Structural and molecular composition of PELNs. This figure illustrates a PELN, typically 50–200 nm in diameter, with a spherical or cup-shaped morphology and a lipid bilayer membrane. Characteristic surface markers include CD63, PEN1, TET8, TET3, Exo70, Class I chitinase (PR-3), and Class I β-1,3-glucanase (PR-2). Internal contents of PELNs consist of cytosolic proteins such as HSP70, GAPDH, nucleic acids (miRNA, RNA), lipids, and other biologically active constituents. The membrane composition mainly includes phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidic acid (PA), which are critical for vesicle stability and cellular uptake. The figure also includes a symbolic legend indicating the molecular components. (By Figdraw).

Due to their low immunogenicity, excellent biocompatibility, inherent targeting capacity, and suitability for surface engineering, PELNs have been widely explored in drug delivery, diagnostics, and therapeutic intervention.^5,10 They have demonstrated promising effects across diverse disease models, including inflammation, oxidative stress, cancer, wound healing,⁸ immune regulation, neuroprotection, metabolic modulation, cardiovascular protection, gut homeostasis, osteoporosis, muscle atrophy, and premature ovarian failure. Notably, PELNs are compatible with multiple administration routes, including oral, intravenous, intratracheal, intranasal, and topical delivery.¹¹ This review therefore provides a comprehensive overview of therapeutic applications and signaling mechanisms associated with PELNs, offering insights to guide future translational research and clinical development.

The Key Therapeutic Applications of Plant-Derived Exosome-Like Nanoparticles

Among the various biomolecules encapsulated in PELNs, miRNAs are key post-transcriptional regulators of gene expression. Their therapeutic potential lies in their ability to mediate cross-kingdom communication, thereby increasing the diversity of miRNAs in mammalian cells and exerting multi-target effects.^12,13 PELNs can protect miRNAs from degradation in the gastrointestinal tract while maintaining specific concentrations. Studies suggest that PELNs contain hundreds of miRNAs, and a single miRNA can target hundreds of mRNAs. Thus, when PELNs levels reach a certain baseline, they may produce significant regulatory effects.¹⁴

For example, ginseng-derived plant exosomes carry mtr-miR159 and deliver it into bone marrow mesenchymal stem cells. This upregulates Tmem100 and activates the PI3K/Akt signaling pathway, promoting neural differentiation and enhancing peripheral nerve regeneration in a rat model of peripheral nerve injury.¹⁵ In another study, ginseng-derived exosome-like nanoparticles delivered their endogenous vvi-miR396b and ptc-miR396f into glioma cells, silencing the oncogenes c-MYC and BCL2, effectively inhibiting tumor growth and achieving efficient blood-brain barrier penetration.¹⁶

Similar to miRNA, small interfering RNA (siRNA) is a double-stranded RNA molecule approximately 20–25 nucleotides in length. It can bind perfectly to the target mRNA and induce its degradation, leading to specific gene silencing. siRNA has important potential for precision therapy, especially in cancer treatment. A typical example is ginger-derived exosome-like nanoparticles (GELNs), which deliver Bcl2 siRNA into tumor cells. By silencing the anti-apoptotic gene Bcl2, they activate the apoptosis pathway in cancer cells and significantly suppress tumor growth in a mouse breast cancer model.¹⁷

PELNs have recently been shown to influence cell fate, inflammatory responses, oxidative stress, tissue repair, metabolic regulation, and tumor immunity through diverse molecular mechanisms.¹⁸ The following studies reveal their considerable potential in disease treatment.

PELNs can regulate cell proliferation, apoptosis, differentiation, and stemness maintenance through multiple signaling pathways and key molecules, thereby contributing to tissue repair, disease therapy, and regenerative medicine. In terms of cell proliferation, PELNs from Momordica charantia are a typical example. They activate the PI3K/Akt and ERK signaling pathways, upregulate PCNA, Cyclin D1, Cyclin B1, and Ki-67, promote cell cycle progression, and enhance cell proliferation, which improves the repair capacity of cardiomyocytes after radiation injury.¹⁹ Regarding apoptosis, PELNs from Brucea javanica carry natural miRNAs (such as the let-7 family) that inhibit the PI3K/Akt/mTOR pathway while activating ROS/caspase-dependent apoptosis, leading to caspase-3 and PARP cleavage. This suppresses tumor cell survival and induces programmed cell death, highlighting the potential of plant exosomes in antitumor therapy.²⁰ In differentiation, PELNs from Panax ginseng activate the PI3K/Akt pathway through miRNAs, significantly upregulate Nestin, β3-tubulin, NGF, BDNF, and bFGF, and drive bone marrow mesenchymal stem cells to differentiate into neurons, providing new insights into neural repair and the treatment of neurodegenerative diseases.¹⁵ In stemness maintenance, PELNs from Grape inhibit GSK-3β activity, stabilize β-catenin nuclear translocation, and activate the Wnt/β-catenin pathway. This induces transcription factors such as c-Myc, Lgr5⁺, SOX2, Nanog, OCT4, and KLF4, which enhance the self-renewal and regeneration of intestinal stem cells.²¹ These studies indicate that PELNs regulate cell cycle factors, apoptosis pathways, differentiation markers, and stemness-related transcription factors, thus playing important roles in cell fate and opening new directions for tissue repair, antitumor therapy, and regenerative medicine.

PELNs also exhibit strong anti-inflammatory and immunomodulatory activities. PELNs from Panax notoginseng inhibit M1 macrophage polarization and promote M2 polarization, reducing TNF-α and IL-6 while increasing IL-10, thereby alleviating inflammation.²² PELNs from Garlic suppress the TLR4/NF-κB pathway, downregulate inflammatory cytokines such as IL-6 and TNF-α, and enhance the tight junction protein ZO-1 to maintain intestinal barrier integrity.²³ PELNs from Broccoli mainly act through the AMPK pathway, promoting tolerogenic dendritic cells and Tregs to restore immune homeostasis.²⁴ These findings suggest that PELNs regulate immune cell phenotypes and cytokine levels through multiple pathways and hold therapeutic potential for inflammatory diseases.

In addition, PELNs demonstrate antioxidative potential. For example, PELNs from Mung bean sprouts activate the PI3K/Akt-Nrf2 pathway to upregulate HO-1 and SOD, and reduce oxidative stress.²⁵ PELNs from Carrot enhance HO-1 and NQO1 via the Nrf2/ARE pathway and decrease ROS production, improving cellular antioxidant defense.²⁶ PELNs from Ginger, which contain 6-Shogaol, also activate Nrf2 and further enhance the ability to scavenge free radicals.²⁷ These mechanisms show that PELNs can effectively strengthen antioxidant capacity, providing new approaches for preventing tissue injury and delaying aging.

In metabolic regulation, PELNs display broad effects. PELNs from Garlic upregulate GLP-1 and IRS1/2, enhance insulin signaling, and improve glucose utilization.²⁸ PELNs from Mung bean sprouts increase GLUT4 expression and decrease GSK-3β activity, promoting glucose uptake and glycogen synthesis and improving insulin resistance.²⁵ PELNs from Citrus limon suppress lipid metabolism genes such as ACACA, DDHD1, and DHCR24, reduce lipid synthesis, and induce tumor cell apoptosis.²⁹ These results indicate that PELNs can improve glucose metabolism, enhance insulin sensitivity, and regulate lipid metabolism, showing promise in the treatment of metabolic diseases.

In immune regulation and antitumor responses, PELNs demonstrate unique mechanisms. Exosomes from Artemisia annua contain plant mitochondrial DNA, which activates the cGAS-STING pathway, enhances IFN-I production, and promotes CD8⁺ T cell activation, thereby improving antitumor immunity.³⁰ PELNs from Catharanthus roseus act through the TNF-α/NF-κB/PU.1 axis to strengthen immune cell function and relieve chemotherapy-induced immunosuppression.³¹ PELNs from Panax ginseng activate TLR4 signaling, drive tumor-associated macrophages toward the M1 phenotype, and enhance local immune activity.³² These studies indicate that PELNs can regulate both innate and adaptive immunity, enhance antitumor responses, and provide new strategies for cancer immunotherapy.

PELNs are currently under clinical investigation for a variety of human diseases. Ongoing clinical trials are evaluating their therapeutic efficacy in the treatment of colorectal cancer (NCT01294072), head and neck cancer (NCT01668849), and IBD treatment (NCT04879810). Table 2 and Table 3 summarize the classification of PELN-based therapies according to disease types and the therapeutic drugs delivered by PELNs, respectively.³³

Table 2 Classification of PELNs Therapies by Disease Types

Table 3 Therapeutic Drugs Delivered by PELNs

Effects of Plant-Derived Exosome-Like Nanoparticles on Disease-Associated Signaling Pathways

PELNs exert therapeutic effects by modulating multiple critical signaling pathways, including PI3K/Akt, NF-κB, Wnt, AMPK, MAPK, the NLRP3 inflammasome, cGAS/STING, and Nrf2/ARE. Through these regulatory axes, PELNs influence key biological processes such as metabolic homeostasis, anti-inflammation, antioxidation, wound healing, neuroprotection, and tumor suppression, thereby offering therapeutic promise in diverse pathological conditions, including diabetes, neurodegenerative diseases, cardiovascular disorders, inflammatory diseases, and cancer.

PELNs activate PI3K/Akt pathway to promote cell survival, proliferation, and metabolic regulation. In metabolic diseases such as diabetes, PELNs enhance Glucose Transporter Type 4 (GLUT4) expression via the PI3K/Akt pathway, thereby improving insulin resistance.²⁵ In neuroprotection (eg, neurodegeneration, ischemic stroke, and ischemia-reperfusion injury), they inhibit apoptosis and maintain blood-brain barrier (BBB) integrity.^22,77,78 This pathway also facilitates wound healing by promoting skin cell proliferation, migration, extracellular matrix secretion, and angiogenesis.⁶⁷ In tumors, PELNs modulate cancer cell survival, proliferation, and metabolism while inhibiting invasion and metastasis.^20,58,59

NF-κB pathway is primarily involved in regulating inflammation, immune responses, and cell survival. In inflammatory diseases (eg, colitis), PELNs downregulate pro-inflammatory cytokines such as TNF-α and IL-6, alleviating inflammation.²³ In bone metabolism disorders (eg, osteoporosis), they inhibit osteoclast activation to reduce bone loss.⁸³ They also enhance immune function (eg, post-chemotherapy immunomodulation) by activating lymphocytes and macrophages,³¹ and contribute to anti-aging effects in skin by promoting collagen expression.⁷²

Wnt signaling pathway regulates cell proliferation, differentiation, and tissue homeostasis. PELNs promote intestinal stem cell proliferation and differentiation via Wnt/TCF4 activation, thus supporting intestinal repair.¹⁰⁴ In inflammatory conditions like colitis, they modulate neural stem cell differentiation in the intestine to enhance regenerative capacity.²¹

AMPK pathway is a master regulator of cellular energy metabolism and homeostasis. In muscle atrophy, PELNs upregulate myogenesis-related factors, enhance metabolic activity, and improve mitochondrial function.⁸⁵ In inflammation (eg, colitis), they attenuate inflammation by suppressing pro-inflammatory cytokines and promoting anti-inflammatory mediators.²⁴

MAPK pathway governs cell proliferation, differentiation, stress responses, apoptosis, and inflammation. In inflammatory liver injury (eg, acetaminophen (APAP)-induced hepatotoxicity), PELNs inhibit phosphorylation of key proteins, reducing hepatocyte apoptosis and inflammation.⁹⁶ In neuroprotection and cardioprotection, they improve cell survival and prevent radiation-induced apoptosis.^19,77 Additionally, they promote tissue regeneration (eg, wound healing), bone remodeling (eg, osteoporosis),^67,82–84 and exert antitumor effects by suppressing proliferation, inducing apoptosis, and reducing tumor cell invasiveness.^29,58

NLRP3 inflammasome regulates innate immunity and the release of pro-inflammatory cytokines. In conditions such as hepatic injury, sepsis-induced acute lung injury, and ulcerative colitis, PELNs inhibit NLRP3 inflammasome assembly, reduce cytokine release, and mitigate inflammatory damage.^{35,42,44,50,105}

cGAS/STING pathway plays a crucial role in innate immunity, antiviral defense, and antitumor immunity. In metabolic disorders such as insulin resistance and type 2 diabetes, PELNs improve metabolic function by reducing inflammation and promoting insulin receptor substrate expression.^28,76 In tumor immunoregulation, they reshape macrophage phenotypes and enhance antitumor immunity, thereby suppressing tumor growth.³⁰

Nrf2/ARE pathway alleviates oxidative stress by upregulating antioxidant defenses. In neurodegenerative diseases (eg, Parkinson’s disease), PELNs reduce oxidative damage and enhance neuronal survival.²⁶ In cardiovascular diseases (eg, myocardial infarction) and inflammatory liver injury (eg, alcoholic fatty liver), they suppress ROS production and induce antioxidant enzymes such as HO-1 and NQO1, thereby reducing tissue injury.^{26,27,79,81,106}

Collectively, PELNs modulate diverse signaling pathways to regulate metabolism, inflammation, oxidative stress, tissue regeneration, and tumor progression, highlighting their broad clinical potential across multiple disease spectrums. (Figure 2).

Table 4 Summary of Signaling Pathways Affected by PELNs

Figure 2 Hierarchical representation of PELNs-regulated signaling pathways and associated diseases. This three-tier circular diagram illustrates the relationship between key signaling pathways modulated by PELNs, the major disease categories they influence, and specific pathological conditions. This three-tier circular figure illustrates the relationship between key signaling pathways modulated by plant-derived exosome-like nanoparticles (PELNs), the major disease categories they influence, and specific pathological conditions. Inner ring (core): Key signaling pathways involved in PELNs-mediated therapeutic effects, including PI3K/Akt, NF-κB, MAPK, AMPK, Wnt, NLRP3 inflammasome, cGAS/STING, Nrf2/ARE, among others. Middle ring: Broad disease categories influenced by the corresponding pathways, such as metabolic disorders, inflammatory diseases, neurodegenerative conditions, cardiovascular diseases, musculoskeletal disorders, cancers, and tissue regeneration. Outer ring: Representative diseases within each category (eg, diabetes, ulcerative colitis, ischemic stroke, myocardial infarction, osteoporosis, TNBC, etc.). The figure highlights the multifunctional regulatory roles of PELNs across diverse pathological contexts. (By Figdraw).

In addition to the major signaling pathways discussed above, several less common but biologically relevant pathways modulated by PELNs have also been identified and are comprehensively summarized in Table 4. With the continued elucidation of the molecular mechanisms by which PELNs regulate intracellular signaling, their application in precision drug delivery is expected to expand significantly. Owing to their low cytotoxicity, high biocompatibility, and minimal intrinsic immunogenicity, PELNs offer a unique therapeutic modality that integrates drug delivery, signaling modulation, and dynamic response to pathological stimuli. This multifaceted functionality enables a synergistic “delivery–regulation–therapy” strategy to enhance therapeutic efficacy. Furthermore, the inherent targeting capacity of PELNs, coupled with their surface modifiability, holds great promise for the development of intelligent drug delivery systems. Such systems would possess disease-site recognition, stimulus responsiveness, and controlled release capabilities, offering a more efficient, safe, and personalized treatment approach for chronic disorders, cancer, and inflammatory diseases.

Beyond signaling pathways, several bioactive molecules have been identified as mediators of PELN function. For example, Houttuynia cordata PELNs contain flavonoids such as luteolin,³⁵ ginger-derived PELNs carry 6-shogaol,²⁷ broccoli-derived PELNs deliver sulforaphane,²⁴ and Artemisia annua PELNs contain mitochondrial DNA,³⁰ engineered ginseng-derived ELNs are loaded with miR-182-5p,⁵⁰ tomato-derived PELNs carry miR164a/b-5p,⁸¹ ginseng-derived nanoparticles contain various miRNAs,¹⁵ Momordica charantia PELNs include miR-5266 and miR-5813,⁷⁸ and Brucea javanica PELNs contain functional miRNAs such as let-7.²⁰ These findings show more clearly which bioactive components of PELNs are responsible for their therapeutic effects.

Future Prospective

With the progress of research on PELNs in drug delivery and disease treatment, their potential as novel therapeutic tools is becoming increasingly evident. Current preclinical studies have demonstrated that PELNs possess low immunogenicity, favorable biocompatibility, and can be given through multiple administration routes. They have shown positive therapeutic effects in models of inflammation, cancer, cardiovascular disease, neurodegeneration, and metabolic disorders. Importantly, PELNs can not only serve as carriers for drugs and nucleic acids (eg, miRNA and siRNA), but also provide therapeutic benefits through their own bioactive components. This dual role makes them promising for complex diseases.

In the future, several challenges still need to be addressed before PELNs can be widely used in clinical practice. First, their therapeutic effects must be reproducible and stable At present, PELNs derived from different plants may show differences in composition and function, and these differences need systematic study. Second, although animal experiments have demonstrated that PELNs can suppress inflammation, reduce oxidative stress, and promote tissue repair, their safety, effective dosage, and long-term benefits in humans remain to be clarified. Furthermore, combining PELNs with existing therapies could further improve outcomes. For example, in cancer therapy, PELNs may serve as natural carriers for nucleic acids and be used in combination with chemotherapy or immune checkpoint inhibitors, which might increase efficacy and reduce side effects.

Looking ahead, PELNs show broad prospects in treatment. They may become not only the next generation of drug delivery platforms, but also independent therapeutic agents. With further progress in preparation methods, mechanistic studies, and clinical validation, PELNs may bring new breakthroughs for the treatment of currently intractable diseases.

Funding

National Natural Science Foundation of China (82405273), Natural Science Foundation of Hubei Province (2022CFD023 and 2024AFD299). Basic scientific research project of the Educational Department of Liaoning Province (JYTMS20230584). Natural Science Foundation of Liaoning Province (2023-MSLH-028).

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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