Tumor Microenvironment-Responsive Nanocluster for Time-Resolved Hyperthermic Intraperitoneal Chemo/Thermal-Therapy against Colorectal Peritoneal Metastasis.

Peritoneal metastasis (PM) originating from gastrointestinal cancer was considered a terminal disease until recently. It poses significant therapeutic challenges due to its diffuse nature and barriers to effective drug delivery. While locoregional approaches such as hyperthermic intraperitoneal chemotherapy (HIPEC) extend survival, their efficacy is constrained by systemic toxicity and tumor thermoresistance. To address these issues, we developed a tumor microenvironment-responsive nanocluster system (MoNs@MyC) for augmented HIPEC treatment. Comprising ultrasmall monodispersed-nanoclusters (MoNs) and clinically used HIPEC drug mitomycin C (MyC), MoNs@MyC self-assembles into microsize particles in acidic PM tumor environments, significantly enhancing localized drug retention during HIPEC. Its photothermal conversion ability enables noninvasive, time-resolved secondary hyperthermia therapy to synergize with chemotherapy and circumvent the thermoresistance of cancer cells. Furthermore, MoNs@MyC selectively mitigates the MyC-induced oxidative damage in healthy tissues. In PM mouse models, MoNs@MyC outperformed conventional MyC-based HIPEC, achieving superior tumor control and stimulating antitumor immunity via T-cell infiltration and pro-inflammatory cytokine upregulation. With scalable synthesis and cost-effective design, this dual-responsive system represents a transformative strategy for precision PM therapy, bridging the gap between localized treatment efficacy and systemic safety.