Injectable self-healing hydrogel delivering trispecific engineered exosomes for osteoporotic bone regeneration via activating mitophagy.

Authors

Ning Xu, Chenjun Liu, Jieyuan Zhang, Huiyong Dai, Shengting Wu, Sa Song, Junjie Guan, Xin Qi, Wei Zhang

Published in

Materials today. Bio. Volume 41. Pages 103780. Epub Oct 27, 2026.

Abstract

Osteoporotic bone defects are characterized by impaired matrix remodeling, diminished osteogenic potential, and insufficient vascularization, posing major challenges for tissue regeneration. Mesenchymal stem cell-derived exosomes (MSCs-Exos) have shown promise in promoting osteogenesis and angiogenesis, but their clinical translation is limited by rapid clearance and lack of targeted delivery. Here, we report the development of an injectable, self-healing SK/HA@A hydrogel for sustained delivery of trispecific RNA-engineered exosomes (Tri-Exos) targeting IL31, CELA1, and PCOLCE2. Tri-Exos were engineered via electroporation and rigorously characterized for morphology, size, marker expression, cellular uptake, and functional regulation of target genes in BMSCs. The hydrogel exhibited rapid gelation, robust mechanical properties, dynamic self-healing, and sustained release of Tri-Exos over 30 days. In vitro, SK/HA@A@EVs significantly enhanced BMSC osteogenic differentiation, matrix mineralization, and HUVEC angiogenic responses, while simultaneously activating mitophagy-mediated mitochondrial regulation and autophagy-associated survival pathways, which are critical for maintaining cellular homeostasis under osteoporotic conditions. In a rat femoral defect model, hydrogel treatment improved bone volume, mineral density, and vascularization, as confirmed by micro-CT, histological analyses, and gene expression profiling. Collectively, these results demonstrate that the SK/HA@A@EVs platform orchestrates osteoporotic bone regeneration through synergistic modulation of osteogenesis, angiogenesis, and mitophagy-driven cellular survival pathways. This study provides a translational strategy integrating engineered exosomes with functional hydrogels for targeted, localized therapy of osteoporotic bone defects.

PMID:
42999764
Bibliographic data and abstract were imported from PubMed on 08 Nov 2026.

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