Cascade-amplified iron-doped bismuth sulfide biomimetic nanoplatform for synergistic therapy and multimodal imaging of triple-negative breast cancer.

Photothermal therapy (PTT) is a promising strategy for cancer treatment, yet traditional high-temperature PTT (>50 °C) often induces heat shock protein (HSP) overexpression and exacerbates tumor hypoxia, particularly in triple-negative breast cancer (TNBC), thereby promoting therapeutic resistance and limiting efficacy. In contrast, mild PTT (<45 °C) has gained increasing attention for its ability to exert therapeutic effects while minimizing damage to surrounding normal tissues. Herein, we developed a biomimetic nanoplatform, tFBSG@M BNPs, to enhance mild PTT through a cascade-amplified synergistic mechanism tailored to the TNBC microenvironment. By coating iron-doped bismuth sulfide nanoparticles with tumor cell membranes for homologous targeting, this nanoplatform integrates three interconnected therapeutic actions: (1) Mild PTT, alleviates hypoxia by improving local blood flow and oxygen supply, both reducing HSP-mediated thermotolerance and preparing the tumor microenvironment for downstream catalysis. (2) Higher oxygen levels boost GOx-mediated starvation therapy, depleting glucose and generating HO, which not only disrupts tumor metabolism but also serves as a substrate for further oxidative amplification. (3) HO is catalytically converted by Fe centers into •OH via a Fenton reaction, unleashing potent oxidative stress that completes the self-amplifying cascade and drives apoptosis. This cascade-driven approach achieved a 96.52 % tumor volume reduction under NIR irradiation. MRI showed a 190 % increase in T1 signal at the tumor site, confirming nanoparticle accumulation; CT provided a 24.7 HU contrast enhancement for clear boundary mapping; and PA imaging visualized tumor vasculature and blood oxygen saturation. By uniting mild PTT, metabolic disruption, and ROS amplification in a single tumor-targeted platform, tFBSG@M BNPs offer a promising strategy to overcome TNBC resistance and improve therapeutic outcomes. STATEMENT OF SIGNIFICANCE: 1. A cascade-amplified therapeutic mechanism that overcomes TNBC's hypoxia, HSP-mediated thermotolerance, and antioxidant defenses through the integration of mild photothermal therapy, GOx-mediated starvation, and Fenton reaction-driven chemodynamic therapy. 2. A multifunctional nanoplatform (tFBSG@M BNPs) that combines iron-doped BiS, glucose oxidase, and homologous tumor membranes, achieving 96.52 % tumor suppression and a 7.4-fold increase in ROS under mild PTT in an orthotopic TNBC model. 3. A clinically adaptable multimodal imaging strategy, combining CT, MRI, and PA imaging in a stepwise fashion to guide therapy with precise boundary mapping, soft tissue resolution, and vascular visualization.