Mesoporous silica-coated gold nanorod grafted with cisplatin prodrug on the surface enhances radiotherapy for cervical cancer via triple-strategy approach.

Concurrent radio-chemotherapy remains the standard treatment for cervical cancer, but its efficacy is limited by tumor hypoxia and enhanced DNA repair in cancer cells. To address these issues, mesoporous silica (MSN)-coated gold nanorod (Au NR) grafted with cisplatin prodrug (MDDP) on the surface and O2-loaded perfluorocarbon (PFC) in the mesopores was constructed (AMPOM). AMPOM has unique surface prodrug doping structure and mesopores that allows it to load cargoes and release active drug and O2 by targeting tumor microenvironment with GSH overexpression under NIR radiation. The high surface area of Au NR@MSN provides excellent drug-loading capacity, ensuring effective MDDP delivery to the tumor site through an amidation reaction. The Au NR core simultaneously enhances radiation dose via high-Z element deposition and generates localized hyperthermia under near-infrared (NIR) irradiation. Tumor-specific release of active cisplatin (CDDP) occurs through MDDP reduction, triggered by the acidic tumor microenvironment and elevated intracellular glutathione (GSH). The released CDDP synergizes with radiotherapy by forming DNA crosslinks that impair DNA damage repair mechanisms, while the photothermal effect of Au NRs under 808 nm NIR further accelerates drug release and increases tumor cell susceptibility to DNA damage. Efficient O₂ delivery alleviates tumor hypoxia, improving treatment efficacy by downregulating hypoxia-inducible factor-1α (HIF-1α) and P-glycoprotein (P-gp), thereby reducing CDDP efflux and enhancing cytotoxicity. In vitro and in vivo studies confirm that AMPOM, under 808 nm NIR irradiation, significantly improves radiotherapy outcomes by promoting DNA damage and relieving hypoxia. By integrating photothermal therapy (PTT), chemotherapy, and radiotherapy (RT), AMPOM offers a potent synergistic approach for cervical cancer treatment.