Pathology-adapted peptide–oligonucleotide nanohybrid mitigates glucocorticoid-induced bone loss

Glucocorticoid-induced bone loss (GIBL) remains a major clinical challenge, manifested by both systemic osteopenia and osteonecrosis of the femoral head under chronic glucocorticoid exposure, yet current therapies are limited in coordinately addressing bone deterioration and vascular impairment. With advances in precision medicine, oligonucleotide therapeutics offer opportunities for pathophysiology-informed intervention. Here, we report a pathology-adapted peptide-oligonucleotide nanohybrid (PON) developed for targeted miR-26a-5p delivery to glucocorticoid-injured bone. By integrating self-assembly, bone targeting, enzyme responsiveness, cell penetration, and lysosomal escape, PONs were designed to incorporate pathology-responsive delivery features and address key barriers to oligonucleotide delivery. Mechanistically, PON-mediated miR-26a-5p delivery reduced GSK-3β expression and promoted HIF-1α stabilization, thereby preserving osteogenesis-angiogenesis coupling and attenuating apoptosis. In a rat model of GIBL, systemic PON administration protects against early skeletal and vascular injury and limits progression after disease establishment. These findings identify the therapeutic relevance of miR-26a-5p in GIBL, and support the potential of PON system for bone-targeted oligonucleotide therapy. Glucocorticoids can cause severe bone loss and osteonecrosis. Here, the authors develop a pathology-adapted peptide–oligonucleotide nanohybrid that delivers miR 26a-5p to mitigate bone loss and support vascular recovery.