A Dual‐Responsive Versatile Nanohybrid Orchestrating Tumor Elimination and Tumor‐Associated Osteolysis Restoration via Sequential Release

ABSTRACT Tumor‐associated bone invasion often occurs in aggressive tumors and strongly compromises the efficacy of tumor treatment, which makes it challenging for comprehensive tumor therapy, highlighting the importance of simultaneous tumor elimination and tumor‐associated osteolysis restoration. To achieve this goal, this study reports a versatile nanohybrid (CaO 2 @CuMOF@HAP) synthesized by coating bimetallic nanoclusters (CaO 2 @CuMOF) with osteogenic growth peptide (OGP)‐modified hyaluronic acid (HAP) for high‐performance oncotherapy. On‐demand sequential release is realized in specific tumor environments, where OGP can be released into matrix metalloproteinase‐9 (MMP9)‐enriched tumor extracellular space through cleavage of the MMP9‐responsive linker between OGP and HA, and dual ions (Cu 2+ and Ca 2+ ) are liberated via pH‐triggered decomposition of the nanohybrid following tumor cell internalization. On the basis of this, small‐sized OGP could penetrate into deep‐seated, tumor‐involved, bone areas for promoting effective osteogenesis, while the excessive ions in targeted tumor cells synergistically disrupted intracellular ion homeostasis for effective metal ion interference therapy. Having killed tumor cells and promoted osteogenesis, CaO 2 @CuMOF@HAP exhibited highly efficient antitumor effects on an orthotopic oral squamous cell carcinoma tumor‐bearing mouse model with mandibular bone invasion. Without cytotoxic drugs, this nanohybrid circumvents drug resistance and nonspecific toxicity, offering excellent biocompatibility and high antitumor efficiency for clinical application.