Effective Osteoporosis Treatment by Polypeptosome-Mediated Neutralization of Acid Bone Microenvironment

The acidification of the bone microenvironment is recognized as a key contributor to osteoporosis. However, current treatment approaches mainly rely on drugs to inhibit osteoclast activity, which often leads to systemic toxicity. Unlike conventional drug-based interventions, we present a polypeptosome (P1:1) that enables “drug-free” osteoporosis treatment by modulating the bone microenvironment. P1:1 was coassembled from poly(ε-caprolactone)37-block-poly(tyrosine)30-block-poly[lysine5-stat-(lysine-zoledronic acid)10] (PCL37-b-PTyr30-b-P[Lys5-stat-(Lys-ZOL)10]) and poly(ethylene oxide)23-block-poly(ε-caprolactone)26 (PEO23-b-PCL26) at a mass ratio of 1:1. The zoledronic acid (ZOL) group endows the polypeptosome with efficient bone-targeting capabilities with a hydroxyapatite (HA) binding rate of 75.3%, while the alkaline polylysine and antioxidant tyrosine segments synergistically restore bone microenvironment homeostasis through pH neutralization and ROS scavenging. In vivo, P1:1 regulates the bone microenvironment by downregulating pH-related genes (including Atp6v0d1) and oxidative stress markers such as lipid peroxidation (LPO) and malondialdehyde (MDA), thus enhancing the bone strength in OVX rats. Transcriptome sequencing further elucidates its therapeutic mechanisms. Overall, P1:1 restores bone microenvironment balance by regulating pH and ROS levels, thereby providing both a therapeutic approach for osteoporosis and insights into bone diseases.