Turn Shield into Sword: Pathological Hydroxyapatite-Targeting Micelles Drive Metabolic Stress-Induced Autophagy Dysfunction for Bone Metastasis Therapy

Abstract Bone metastasis remains a major clinical challenge in advanced breast cancer because therapeutic efficacy is limited by poor lesion targeting and systemic toxicity. Moreover, the hypoxic bone microenvironment induces protective autophagy in tumor cells, which maintains metabolic homeostasis and limits therapeutic efficacy. Herein, we develop a bone metastasis-targeted micellar system (AD/R) to overcome this protective autophagy “shield”. Based on the low crystallinity of pathological hydroxyapatite (HAP) and the hypoxic bone microenvironment, a pathological HAP-targeting polymer (DSPE-PEG-ALN, DPA) and a hypoxia-responsive polymer (DSPE-AZO-PEG, DAP) are coassembled into micelles encapsulating the oxidative phosphorylation inhibitor resveratrol (RES). Following selective accumulation in bone-metastatic lesions, AD/R undergoes hypoxia-triggered disassembly. The released DPA induces calcium-mediated membrane mineralization to restrict oxygen and nutrient supply, whereas RES suppresses oxidative phosphorylation and ATP production. This “external blockade” and “internal disruption” synergistically aggravate metabolic stress, activate AMPK-dependent autophagy, and impair lysosomal degradation through lysosomal membrane permeabilization, ultimately inducing autophagy dysfunction and autophagy-associated tumor cell death. In murine breast cancer bone metastasis models, AD/R effectively suppresses bone and secondary lung metastases and restores bone homeostasis. This work establishes a “turn shield into sword” paradigm by converting protective autophagy into metabolic stress-induced autophagy dysfunction for the treatment of bone metastasis.