Bone-targeted acid-responsive polyphosphazene-based resveratrol self-framed delivery system with superior efficacy for osteoporosis treatment in ovariectomized mice

Bone-targeted acid-responsive polyphosphazene-based nanodrug was constructed and obvious enhancement of anti-osteoporosis efficacy was achieved. • Bone-targeted acid-responsive polyphosphazene-based nanodrug was facilely constructed. • HCCP-Res-PEG-ALN (HRPA) shows high water dispersity, desirable bone-targeting capability. • HRPA exerts dual functions via inhibiting osteoclasts and promoting osteoblasts in vitro. • HRPA shows obvious enhanced efficacy for osteoporosis treatment in ovariectomized mice. Osteoporosis (OP) is a severe chronic metabolic bone disorder characterized by a reduction in bone mass and the deterioration of bone microarchitecture with increasing risk of fragility fractures. To date, long-term management and therapy of OP is still a challenge and development novel, efficient and economic treatment options is urgently required. Resveratrol (Res) is a polyphenolic compound with great potential for OP treatment via accelerating bone generation and inhibiting bone resorption. However, its undesirable bioavailability resulting from low water solubility and poor stability will undoubtably restrict its efficacy. In this study, we address the challenge of targeted drug delivery for osteoporosis treatment by developing a bone-targeted, acid-responsive polyphosphazene-based resveratrol self-framed delivery system. This system leverages the acidic microenvironment of bone tissue to trigger drug release, enhancing therapeutic efficacy and reducing side effects. We hypothesize that the incorporation of resveratrol into a polyphosphazene framework will provide controlled release and improved bioavailability. Our results demonstrate that this delivery system significantly enhances bone density and biomechanical properties in ovariectomized mice, with minimal adverse effects. This innovative approach holds promise for the development of more effective osteoporosis therapies.