Osteoporosis treatment via programmed delivery of IRF5 siRNA to macrophages in bone tissue combined with ROS scavenging

Postmenopausal osteoporosis (PO) is not merely a consequence of increased osteoclast activity. Estrogen deficiency induces oxidative stress and pro-inflammatory M1 macrophage polarization in bone tissue, thereby sustaining osteoclastogenic stimuli and pathological bone resorption. Interferon regulatory factor 5 (IRF5) is a key regulator of M1 polarization, and silencing its gene by small interfering RNA (siIRF5) may attenuate the pathogenesis of PO. However, selective delivery of siIRF5 to M1 macrophages within the osteoporotic bone microenvironment is challenging. Herein, we develop a nanomedicine, termed siP@WM, for programmed sequential targeting of bone tissue and macrophages. The siP@WM integrates a platinum nanozyme core with mesoporous silica shell loading siIRF5. The shell with enlarged pores (10–15 nm) provides effective siRNA encapsulation and programmable surface grafting of two kinds of poly(ethylene glycol) (PEG) derivatives. The longer poly(aspartic acid)-terminated PEG chain promotes bone enrichment. ROS-triggered thioketal cleavage shortens this chain, reduces bone-matrix adhesion, and exposes the shorter folic acid-functionalized PEG chain to enhance M1 macrophage uptake. In vitro , siP@WM scavenges ROS, facilitates endosomal escape, achieves approximately 60% IRF5 knockdown, and promotes M2 polarization. In ovariectomized mice, systemic administration of siP@WM ameliorates bone loss, restores trabecular microarchitecture and mechanical strength, and shows no overt short-term toxicity in major organs. Transcriptomic and histological analyses support attenuated AP-1-associated inflammatory signaling, suppressed osteoclast differentiation, and modulated extracellular matrix remodeling. Together, programmed siIRF5 delivery to macrophages in bone tissue combined with ROS scavenging restores bone homeostasis and provides an adaptive biomaterial strategy for PO treatment.