Multifunctional biodegradable nanoplatform based on oxaliplatin prodrug cross-linked mesoporous polydopamine for enhancing cancer synergetic therapy

Due to the limitations of conventional chemotherapy including side effects, poor prognosis, and drug resistance, there is an urgent need for the development of a novel multi-functional combined therapy strategy. Dopamine-modified oxaliplatin prodrug (OXA-DA) was successfully synthesized in this study to ameliorate the organ distribution of oxaliplatin for improving the drug efficacy and reducing toxic side effects, and OXA-DA was applied to develop a porous oxaliplatin cross-linked polydopamine nanoparticle for loading siPD-L1 to construct multifunctional nanoplatform. The multifunctional nanoplatform was modified with poly(2-ethyl-2-oxazoline) (PEOz), which occurred charge reversal in the tumor microenvironment, and exerted the lysosomal escape effect in tumor cells to improve the bioavailability of small interfering RNA targeting programmed cell death-ligand 1 (siPD-L1). The pH-responsive charge reversal, photothermal, biodegradation, lysosomal escape ability, PD-L1 protein degradation, toxicity properties and multiple antitumor effects were comprehensively evaluated in vitro and in vivo experiments. The findings indicated that OXA-DA-siPD-L1@PDA-PEOz excellently induced tumor cell necrosis and apoptosis as a result of the synergistic effect of chemo-photothermal therapy, and upregulated CD8+ T cells produced interferon-γ (IFN-γ) to further attack the tumor cells. In conclusion, the novel nanoplatform-mediated chemo/photothermal/immunotherapy has promising clinical applications in the treatment of malignant tumors.