Nucleic acid-based nanogels with “offensive and defensive”effects for enhanced chemo-immunotherapy

Chemotherapeutic drugs such as doxorubicin (DOX) can activate CD8⁺ T cell-mediated antitumor immune responses by inducing immunogenic cell death (ICD), demonstrating the potential of chemo-immune synergistic therapy. However, the continuous stimulation of tumor antigens triggers the exhaustion of CD8⁺ T cells, which has become the main obstacle to inhibiting tumor growth and metastasis. Dual regulation of T cell infiltration and exhaustion to elicit a robust immune response is the key for optimizing tumor immunotherapy. In this study, a membrane-coated framework nucleic acid-based nanogel (RM@NG/DOX) was developed to co-deliver DOX and siRNA (siTOX, thymocyte selection-associated high mobility group box protein, TOX) for the spatiotemporal synergistic regulation of chemo-immunotherapy. This system broke the traditional cationic carrier mode of siRNA delivery and constructed a double-layer barrier to further protect the loaded siTOX and DOX. RM@NG/DOX induced ICD by DOX as an “offensive” signal to enhance T cell infiltration, while siTOX as a “defensive module” reversed the differentiation of exhausted T cells (PD-1⁺ Tim-3⁺) by silencing TOX, a key regulator of T cell exhaustion. Experiments in vitro and in vivo confirmed that RM@NG/DOX reshaped the immune microenvironment through the dual pathway of “activation-reversal” to effectively inhibit tumor growth and metastasis, successfully transforming the “cold tumor” into an immune-infiltrated “hot tumor” and enhancing chemo-immunotherapy. In summary, the combined chemo-genetic nanomedicine based on nucleic acid nanogels provides a new strategy for chemo-immunotherapy and the regulation of T cell exhaustion.