What makes PELNs unusual is that they possess intrinsic biological activity rather than simply ferrying externally loaded drugs. Unlike synthetic nanoparticles, whose therapeutic effects depend on whatever cargo has been chemically attached, PELNs arrive prepackaged with endogenous molecules that can influence gene expression, intracellular signaling and metabolic adaptation in recipient cells. Plants release these vesicles through multiple intracellular membrane trafficking routes, including multivesicular bodies, exocyst-positive organelles, vacuolar trafficking and plasma membrane budding, which explains why different PELN preparations vary so widely in size, membrane composition and molecular cargo. This heterogeneity is both a strength and a challenge. It gives each vesicle type a distinct biological signature, but it also makes standardization across laboratories difficult.

The translational appeal is hard to ignore. PELNs can be isolated from edible fruits, vegetables and medicinal plants using scalable, cost-effective procedures, sidestepping many of the biosafety, pathogen transmission and ethical concerns associated with animal-derived materials. They also show remarkable physicochemical stability, maintaining structural integrity under simulated gastrointestinal conditions and following oral administration in preclinical models. Experimental studies have demonstrated that orally administered ginger-derived and grape-derived nanovesicles survive gastrointestinal transit, get internalized by intestinal epithelial cells and resident immune cells, and exert therapeutic effects in models of intestinal inflammation. This stability and bioavailability compare favorably with many synthetic nanocarriers.

The review highlights several striking examples of PELN-mediated tissue repair. In skeletal muscle, goji berry-derived nanovesicles attenuated dexamethasone-induced muscle atrophy by activating the AMPK/SIRT1/PGC-1α signaling pathway, which promoted mitochondrial biogenesis and improved energy metabolism. In bone, Panax ginseng-derived nanovesicles enhanced osteoblast-associated activity and bone-forming capacity in osteoporosis-related models. Sea buckthorn-derived extracellular vesicles promoted osteogenic differentiation of bone marrow mesenchymal stromal cells and improved bone defect repair in murine femoral models. Paris polyphylla-derived vesicle-like particles enhanced periodontal ligament stem cell proliferation, migration and osteogenic differentiation, accelerating alveolar bone regeneration. Turmeric-derived nanovesicles reprogrammed pathological NETosis to mitigate inflammatory bone destruction, illustrating how PELNs can reshape immune behavior at the bone-immune interface.

Cartilage repair, one of the most stubborn challenges in regenerative medicine, has also attracted PELN attention. Grapefruit-derived plant extracellular vesicles regulated chondrocyte metabolic activity by enhancing anabolic responses while suppressing catabolic factors associated with cartilage degradation. These vesicles also promoted chondrocyte migration, suggesting that PELNs may support cartilage repair by improving cellular mobility within damaged joint tissue. Compared with muscle and bone, however, the evidence base for PELN-based cartilage repair remains relatively limited, and further studies are needed to clarify tissue targeting mechanisms, cargo-specific functions and long-term therapeutic effects in clinically relevant osteoarthritis models.

Peripheral nerve repair offers perhaps the most mechanistically detailed example. Salvia miltiorrhiza-derived extracellular vesicles were investigated in a peripheral nerve injury model and showed regenerative effects involving macrophage stress responses and angiogenic signaling. Following nerve injury, macrophages recruited to the site clear myelin debris and support vascular remodeling, but excessive debris uptake can induce lipid peroxidation and ferroptotic stress, impairing their regenerative function. The Salvia vesicles alleviated macrophage ferroptosis by enhancing expression of ferroptosis-resistance regulators, including ferritin heavy chain 1 and glutathione peroxidase 4, while reducing the ferroptosis-associated factor ACSL4. This regulation decreased lipid peroxidation, restored pro-regenerative macrophage activity and enhanced angiogenic signaling, including restoration of VEGFA expression and increased vascularization. These changes coincided with enhanced Schwann cell migration and axonal regeneration, linking macrophage stress regulation with vascular and neural repair in a single experimental model.

Beyond individual tissue effects, the review proposes an immune-metabolic-mitochondrial framework to explain how PELNs might work. Macrophages provide a well-studied example of this crosstalk. Inflammatory activation is often accompanied by greater reliance on glycolysis, whereas repair-associated states generally involve greater mitochondrial oxidative metabolism. These states are not fixed, however, and macrophage metabolism changes with local signals, nutrient availability and redox conditions. Tissue repair therefore depends on the appropriate transition between inflammatory and reparative states rather than simply on suppression of inflammation. Ginger-derived exosome-like nanoparticles, for example, inhibited NF-κB signaling in intestinal epithelial cells and suppressed NLRP3 inflammasome activation in macrophages, while grape-derived vesicles interacted with intestinal Lgr5-positive stem cells and promoted Wnt/β-catenin-associated epithelial regeneration. These studies show that plant-derived nanovesicles can act on both inflammatory and regenerative cell populations, although they do not establish that the two effects are metabolically coupled.

The review is careful to acknowledge significant limitations. PELNs from different plant species vary substantially in composition, and most have been studied in different cell types, disease models and experimental settings. Findings obtained with one vesicle preparation cannot be assumed to apply to PELNs as a whole. Many studies identify RNAs, proteins, lipids or phytochemicals in PELNs and report downstream signaling changes, but relatively few directly show that a specific cargo is responsible for the observed effect. Loss-of-function experiments, cargo depletion and rescue approaches remain uncommon. The same caution applies to mechanisms inferred from non-musculoskeletal models. Whether endogenous plant miRNAs directly regulate mammalian target genes under physiologically relevant conditions remains controversial, with concerns about interaction specificity, detection of very low-abundance plant miRNAs and the possibility of contamination or analytical artifacts during RNA extraction and sequencing.

Standardization presents a practical barrier to comparing PELNs across studies. Plant species, cultivar, tissue type, maturity, growing conditions, storage and sample processing all affect the composition of the starting material. Mechanical disruption during juice extraction or tissue homogenization adds another source of variation because intracellular membranes and other plant-derived particles may enter the vesicle-containing fraction. Isolation methods add a second layer of variation. Differential centrifugation and ultracentrifugation are widely used but can co-isolate non-vesicular material and promote aggregation. Density-gradient centrifugation improves separation but costs longer processing and sometimes lower recovery. Size-exclusion chromatography reduces contamination by soluble proteins but suffers from sample dilution and incomplete separation from similarly sized particles. No single method provides optimal yield, purity and scalability, and combinations of complementary approaches may be preferable when highly purified preparations are required.

Engineering strategies are driving the evolution of PELNs from naturally occurring biological vesicles toward programmable regenerative nanoplatforms. Polydopamine coating represents one of the most successful examples. Apple-derived extracellular nanovesicles coated with polydopamine and chelated with gadolinium exhibited enhanced blood-brain barrier penetration, promoted microglial M2 polarization, reduced infarct volume and simultaneously enabled MRI-guided therapy in ischemic stroke models. Surface functionalization through PEGylation improves colloidal stability, reduces nonspecific clearance and prolongs systemic circulation. Ligand-mediated targeting, in which peptides, antibodies, aptamers or small molecules are conjugated onto vesicle membranes, remains in its infancy for PELNs but represents an important future direction. Functional cargo loading has also been demonstrated, with PELNs successfully loaded with dexamethasone, microRNA-124 and small interfering RNAs. Dexamethasone-loaded Allium tuberosum-derived nanovesicles exhibited stronger suppression of microglial inflammation than either free dexamethasone or native vesicles, while erythrocyte membrane-fused Panax notoginseng-derived nanovesicles markedly prolonged circulation time and enhanced miR-124 delivery across the blood-brain barrier.

Biomaterial-assisted delivery offers another promising direction for localized regenerative rehabilitation. Hydrogels enable sustained release, protect vesicles from degradation and maintain high local concentrations at injury sites. Three-dimensional scaffolds can combine mechanical support with biological signaling, and incorporation of PELNs into porous scaffolds may facilitate stem cell recruitment, extracellular matrix remodeling and vascular ingrowth during bone regeneration. Peripheral nerve repair represents another attractive application, with advanced nerve guidance conduits, including polycaprolactone-based conduits, conductive scaffolds and carbon quantum dot-modified biomaterials, demonstrating excellent capacity to support axonal guidance, Schwann cell migration, angiogenesis and functional nerve regeneration. Although direct integration of PELNs into these platforms has not yet been extensively explored, the intrinsic immunomodulatory and pro-regenerative properties of PELNs suggest they could serve as bioactive cargos to further optimize the regenerative microenvironment.

The connection to exercise and rehabilitation remains largely unexplored but biologically plausible. Acute physical activity increases the release of circulating extracellular vesicles, and exercise-responsive vesicles carry proteins that may participate in communication between metabolically active tissues. This does not mean that exercise-derived mammalian vesicles and PELNs are functionally equivalent. They differ in origin, composition and biological context. The connection is instead based on the processes they may influence. PELNs have been reported to affect inflammatory signaling, redox balance, mitochondrial function and regenerative cell responses, many of which are also involved in tissue adaptation to exercise and recovery after musculoskeletal injury. Whether PELN treatment can improve muscle strength, endurance, gait, neuromuscular function, joint mobility or recovery after exercise has rarely been examined, and addressing these questions will require experimental designs that combine PELN treatment with defined exercise or rehabilitation protocols and include functional endpoints alongside molecular and tissue-level measurements.

Pharmacokinetic behavior is another major uncertainty. Although selected PELN systems have been detected in different organs or shown to cross specific biological barriers in preclinical models, quantitative data on absorption, circulation, tissue exposure, clearance and dose-response relationships remain limited. This is particularly relevant to musculoskeletal applications, where the amount of administered PELNs that reaches muscle, bone, cartilage or injured peripheral nerves is often unknown. Most available studies have demonstrated therapeutic efficacy without systematically characterizing vesicle pharmacokinetics, tissue accumulation or clearance profiles. Consequently, whether native PELNs possess intrinsic tropism for musculoskeletal tissues remains unknown. Future studies integrating quantitative fluorescence imaging, radionuclide labeling, single-vesicle tracking and pharmacokinetic analyses will be essential to define tissue distribution, cellular uptake and long-term biodistribution following systemic administration.

Clinical evidence remains far behind the rapidly expanding preclinical literature. Most PELN studies have been conducted in cell culture or animal models, and evidence from human intervention studies is still scarce. For regenerative rehabilitation in particular, clinical development will require more than demonstration of molecular or histological effects. Trials will need to define clinically meaningful outcomes, including physical function, pain, mobility, muscle performance or other tissue-specific endpoints, depending on the intended indication. Regulatory classification presents an additional challenge because PELNs combine features of naturally derived biological materials, nanoscale delivery systems and, in some cases, engineered therapeutic products. Requirements for identity, purity, potency, safety, manufacturing consistency and storage stability will need to be defined according to the final product and intended use. Engineered PELNs may face additional regulatory requirements because surface modification, exogenous cargo loading or incorporation into biomaterials changes the composition of the original plant-derived preparation.

The immune-metabolic-mitochondrial network proposed in the review has not been demonstrated as a complete pathway within a single PELN system. Current studies usually examine selected parts of this network, such as inflammatory signaling, mitochondrial stress or metabolic regulation. Establishing causal links among these processes will require experiments that measure them in parallel and test whether disrupting one component alters the others and changes regenerative outcomes. Until then, the framework is best viewed as a model that organizes the available evidence and defines questions for future study, rather than a fully established mechanism of PELN action. Future work should move from descriptive associations toward causal mechanisms, combining single-cell or spatial profiling with quantitative biodistribution and cargo tracing to identify the cells that encounter and internalize PELNs in vivo and define how these responses change during repair.

PELNs are emerging as bioactive nanovesicles with potential applications in musculoskeletal regeneration, but the strength of evidence varies across tissues. Current evidence indicates that they can influence inflammatory and redox responses, mitochondrial function and regenerative cell activity, although direct evidence for improvements in functional endpoints remains limited. Further progress will depend on establishing causal mechanisms, standardized production and quality control, and clinically relevant functional outcomes. Addressing these gaps will be essential to determine the role of PELNs in regenerative rehabilitation and their potential for clinical translation. For now, the idea that a nanoscale bubble from a goji berry could help rebuild a wasting muscle, or that a vesicle from Salvia miltiorrhiza could coax a damaged nerve to regrow, remains firmly in the realm of experimental biology. But the convergence of cross-kingdom communication, nanoscale engineering and regenerative medicine is opening a genuinely novel therapeutic frontier, one where the boundary between food, medicine and tissue repair begins to blur.

Subject of Research: Plant-derived extracellular nanovesicles emerge as bioactive regulators of musculoskeletal repair, coordinating mitochondrial, immune and metabolic networks across muscle, bone, cartilage and peripheral nerve models.

Article Title: Plant-derived extracellular nanovesicles in musculoskeletal repair and functional rehabilitation: mitochondrial–immune–metabolic regulation

Article References: Zhu, N., Wang, N., Zhou, N., Ye, B., & Liu, J. (2026). Plant-derived extracellular nanovesicles in musculoskeletal repair and functional rehabilitation: mitochondrial–immune–metabolic regulation. Frontiers in Chemistry, 14, Article 1968520. https://doi.org/10.3389/fchem.2026.1968520

Image Credits: AI Generated

DOI: 10.3389/fchem.2026.1968520

Keywords: plant-derived extracellular nanovesicles, musculoskeletal regeneration, mitochondrial reprogramming, immunometabolism, regenerative rehabilitation, tissue repair, Plant-derived, extracellular, nanovesicles, musculoskeletal, repair, functional