Stimuli-Responsive Calcium Phosphate Nanoreactor for Synergistic Chemo-Photothermal-Ferroptosis Therapy of Colorectal Cancer.

BACKGROUND: Colorectal cancer therapy encounters major obstacles, including insufficient tumor targeting, systemic toxicity, and the emergence of drug resistance, underscoring the need for advanced therapeutic modalities. This work aimed to engineer a multi-mechanism synergistic nanoplatform to surmount these limitations. METHODS: A hyaluronic acid-modified calcium phosphate nanoparticle construct (CaPHDH) was developed incorporating a dual-action mechanism via calcium ion chelation and hydrophobic entrapment. Hemin was encapsulated within the calcium phosphate lattice via a green synthesis approach, followed by electrostatic loading of doxorubicin (DOX). The nanoparticles were comprehensively characterized for physicochemical properties. Antitumor efficacy was assessed in vitro in CT26 colorectal carcinoma cells and in vivo in a CT26 tumor-bearing murine model, with or without 808 nm laser irradiation. Mechanistic investigations, including ferroptosis and immune activation, were conducted. RESULTS: The CaPHDH nanoparticles exhibited a uniform size of approximately 100 nm, excellent dispersibility, pH-triggered drug release, and high photothermal conversion efficiency. In vitro, treatment produced a markedly enhanced anti-tumor effect against CT26 cells under 808 nm laser irradiation, attributable to the synergistic actions of chemotherapy, photothermal therapy, and ferroptosis induction. In vivo, CaPHDH achieved effective tumor-specific accumulation and, upon laser irradiation, yielded superior tumor growth inhibition relative to monotherapies. In addition, CaPHDH treatment significantly promotes the polarization of tumor-associated macrophages (TAMs) toward the M1 phenotype, thereby reshaping the tumor immune microenvironment. Comprehensive biosafety assessments indicated no significant systemic toxicity, organ damage, or abnormal alterations in standard blood biochemical parameters. CONCLUSION: This study successfully developed a biosafety-optimized nanodelivery platform, CaPHDH, which integrates chemotherapy, photothermal therapy, and ferrocide induction. This platform enables highly effective synergistic treatment in a mouse rectal cancer model, offering new insights into combination therapy strategies for tumors.