HAMA microneedles patch loaded with muscle-targeting engineered apoptotic vesicles and attenuating sarcopenia by regulating mitochondrial homeostasis.

BACKGROUND

Sarcopenia is an age-related disorder characterized by the progressive loss of skeletal muscle mass and function, primarily driven by mitochondrial dysfunction, oxidative stress, and impaired satellite cell activity. Conventional therapeutic strategies have shown limited efficacy in restoring muscle performance. Apoptotic vesicles (ApoVs) derived from mesenchymal stem cells (MSCs) have recently emerged as promising therapeutic agents capable of delivering bioactive cargos to regulate cellular metabolism and attenuate tissue aging. However, the targeted delivery and functional stability of ApoVs remain major challenges.

RESULTS

We engineered human umbilical cord MSC-derived ApoVs with the muscle-specific aptamer A01B and encapsulated them in a methacrylated hyaluronic acid (HAMA) hydrogel microneedle patch to enhance tissue targeting and enable sustained release. In vitro, ApoVs were efficiently internalized by C2C12 myotubes and alleviated dexamethasone-induced atrophy by promoting proliferation, reducing oxidative stress, restoring mitochondrial structure and function, and modulating the PTEN-PI3K-AKT signaling pathway. miRNA profiling identified miR-21-5p as a key ApoV-delivered effector that activates this pathway. In vivo, treatment with the aptamer-functionalized ApoV microneedle system significantly improved muscle mass, myofiber cross-sectional area, mitochondrial oxidative capacity, and functional endurance in sarcopenic mice compared with controls.

CONCLUSIONS

Our findings demonstrate that the muscle-targeted delivery of engineered ApoVs via HAMA microneedles effectively reverses key hallmarks of sarcopenia by restoring mitochondrial homeostasis and activating PI3K/AKT signaling through miR-21-5p. This microneedle-based ApoV platform provides a promising cell-free therapeutic strategy for ameliorating muscle atrophy and functional decline.