Surface‐Engineered Mitochondrial Extracellular Vesicles for Enhanced Endosomal Escape and Alleviation of Osteoarthritis‐Associated Neuropathic Pain

ABSTRACT Mitochondrial transfer has emerged as a promising therapeutic strategy for disease driven by neural and pain‐related pathologies. However, inefficient intracellular delivery and severe lysosomal degradation significantly limit its translational potential. Given the critical role of mitochondrial dysfunction in Schwann cells (SCs) and macrophages during neuropathic pain progression in temporomandibular joint arthritis and knee osteoarthritis, this study presents an optimised nanomedicine treatment approach using mitochondria‐derived extracellular vesicles (MitoEVs). Here, we isolated functional MitoEVs from SCs for surface modification with a novel micellar material, R 8 ‐HDA (yielding R‐MitoEVs), to enhance efficient endosomal escape. Our results demonstrate that R‐MitoEVs exhibit augmented cellular uptake and enhance evasion of lysosomal degradation, thereby preserving the structural integrity and bioactivity of the transferred mitochondria. Consequently, R‐MitoEVs suppressed lipopolysaccharide‐induced pro‐inflammatory macrophage polarisation and downregulated TNF‐α/NF‐κB signalling. Concurrently, the R‐MitoEV‐derived mitochondria restored metabolic homeostasis in SCs by quenching reactive oxygen species and augmenting antioxidant capacity. In vivo evaluations demonstrated the therapeutic efficacy of R‐MitoEVs, characterised by enhanced chondrocyte resilience and the significant downregulation of pain‐related neuronal markers (TRPV1 and CGRP) and pro‐inflammatory mediators. Overall, this surface‐engineered R‐MitoEVs platform mitigates the biological barriers of mitochondrial delivery, offering a promising therapeutic strategy for mitigating osteoarthritis and its associated neuropathic pain.