Tumor-Selective Autophagy Blockade of Renal-Clearable Bi₂S₃ Nanoflowers for Precise Photothermal Therapy

Conventional strategies rely on complex surface modifications rather than leveraging the intrinsic biological behavior of nanomaterials to achieve tumor selectivity. Here, we introduce a biological behavior-driven nanoplatform, Bi₂S₃@3-MA, in which Bi₂S₃ nanoflowers are engineered by simple surface conjugation with an MMP2-responsive 3-methyladenine peptide (3-MA) to achieve selective tumor cell death. Midsized Bi₂S₃@3-MA (370 nm) preferentially accumulates in tumor tissue. In the tumor microenvironment (TME), elevated MMP2 expression cleaves the peptide linker, triggering the TME-specific release of the autophagy inhibitor 3-MA. This tumor-selective autophagy blockade promotes the aggregation of Bi₂S₃ nanoflowers into micron-scale structures within the acidic lysosomal milieu, culminating in the lysosomal membrane disruption of tumor cells. Furthermore, micron-scale aggregates in tumor cells exhibit enhanced photothermal ablation, overcoming protective autophagy-induced resistance to hyperthermia. In contrast, the rapid renal clearance of pH-responsive degraded particles (pH ∼ 6.5-7.4) minimizes off-target exposure of normal tissues, and protective autophagy preserves the lysosomal integrity of normal cells. Bi₂S₃@3-MA mediates complete tumor eradication in murine breast cancer models through the synergistic combination of photothermal ablation and autophagy inhibition. Additionally, the inherent CT contrast of Bi₂S₃ permits real-time visualization of nanoparticle biodistribution and treatment response. Collectively, these results establish a paradigm in which the deliberate integration of intrinsic biological behavior affords highly selective cancer therapy while minimizing systemic toxicity.