A functionalized lignin dual network nanoplatform for enhanced cancer therapy by triggering reactive oxygen species self-circulation

Reactive oxygen species-based chemodynamic therapy overcomes the tissue penetration limitations inherent in traditional photodynamic therapy and sonodynamic therapy for tumor treatment, thereby garnering significant attention. However, the transient nature of reactive oxygen species and the nonspecific release of chemotherapeutic agents remain great challenges in chemodynamic therapy. In this study, a dual-network nanosystem based on ellagic acid-modified lignin grafted with vinyl pyrrolidone copolymer and loaded with paclitaxel (EAMLVP@PTX) is constructed. While exposed to the acidic tumor microenvironment, the nanoparticles undergo a charge reversal, inducing cationic endocytosis of tumor parenchymal cells. Furthermore, ellagic acid units endow the nanosystem with mitochondrial targeting capability in colon cancer cells. Consequently, reactive oxygen species is produced, resulting in the partial activation of the dynamic network within the nanosystem and further release of anti-cancer drugs, which in turn generates additional reactive oxygen species. This creates a self-sustaining reactive oxygen species cycle, initiating programmed cell death to enhance anti-tumor treatment under sustained oxidative stress. Both in vitro and in vivo experiments demonstrate that the nanosystem exhibits significant antitumor efficacy against colon cancer, with minimal side effects observed. The EAMLVP@PTX effectively addresses the challenges associated with the short life of reactive oxygen species and the specificity of drug delivery, and demonstrates prominent chemo/chemodynamic synergistic therapeutic effects, thereby offering a highly promising strategy for cancer treatment.