Ultrasound‐Triggered Cascade Delivery via Poly‐Oxaliplatin Nanoparticles for Immunotherapy

Abstract Oxaliplatin (OXA), a third‐generation platinum‐based chemotherapeutic agent, is widely utilized in cancer treatment due to its potent cytotoxic effects and its ability to induce immunogenic cell death (ICD). However, the clinical application of OXA is significantly hindered by inefficient drug delivery. To address these challenges, a cascade delivery system that integrates ultrasound (US) activation with Poly‐Oxaliplatin nanoparticles (OXA‐Ce6 NP) is developed to enhance therapeutic efficacy and overcome resistance mechanisms of OXA. This sono‐responsive platform consists of an amphiphilic polymer incorporating an OXA(IV) prodrug (Poly‐OXA(IV)) and the sonosensitizer chlorin e6 (Ce6), enabling a US‐triggered activation cascade. Upon US exposure, this system facilitates 1) enhanced cellular uptake via increased membrane permeability, 2) in situ activation of OXA(IV) through electron transfer, and 3) augmented formation of OXA‐DNA adducts, thereby intensifying DNA damage and cytotoxic effects. Moreover, US‐induced reactive oxygen species (ROS) further potentiate ICD, remodeling the tumor immune microenvironment and promoting systemic antitumor immunity. By leveraging US as an external stimulus, this cascade system enhances the therapeutic outcome of OXA while mitigating resistance and toxicity. This strategy provides a versatile approach to optimizing chemotherapy and integrating immunotherapy, offering a promising avenue for improving the efficacy of cancer treatments.