Clinical-Inspired Design of Self-Assembled Albumin-CeO Nanozymes for Oxygen-Self-Sufficient and Targeted Sonodynamic-Chemotherapy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype with rapid progression, high metastatic risk, and limited treatment options. Clinical TNBC specimens show severe hypoxia along with elevated expression of secreted protein acidic and rich in cysteine (SPARC). Inspired by these patient-derived hallmarks, it is engineered targeted self-assembled albumin-cerium oxide nanozymes (ACCD NPs) that couple SPARC-mediated tumor targeting with catalytic hypoxia modulation for synergistic sonodynamic-chemotherapy. Albumin enables selective delivery of doxorubicin (DOX) and chlorin e6 (Ce6) via SPARC-receptor interactions, while oxygen vacancy-engineered cerium oxide (CeO) decomposes endogenous hydrogen peroxide to generate oxygen, alleviating hypoxia. This oxygenation markedly amplifies ultrasound-triggered reactive oxygen species production, potentiating Ce6-mediated sonodynamic cytotoxicity and enhancing DOX chemosensitivity. In vitro, ACCD NPs demonstrate efficient targeted uptake, lysosome-responsive DOX release, and strong synergistic killing under ultrasound irradiation. In vivo, they achieve 3.8-fold higher tumor accumulation than free drugs, suppress TNBC growth by 84.9%, and downregulate hypoxia-inducible factor-1α (HIF-1α) without systemic toxicity. Mechanistic analyses reveal activation of autophagy and pyroptosis, suppression of oncogenic signaling, and upregulation of tumor suppressor genes. This clinically informed nanoplatform establishes a versatile therapeutic paradigm that translates patient tissue-derived molecular features into precise, multimodal strategies for overcoming hypoxia-associated, treatment-refractory cancers.