Gemini nanoparticles-based quadruple therapy (GNQT) achieved effective tumor immunotherapy by comprehensive regulation of tumor microenvironment

Even though immune checkpoint blockade (ICB) therapy has advanced cancer immunotherapy greatly due to its quick development, and scientists have also tried a variety of combination therapies to further amplify the therapeutic impact, the therapeutic outcome is still limited because of the complex immunosuppressive microenvironment of tumor tissue. To improve the antitumor effect of immunotherapy, developing more comprehensive and effective tumor microenvironment regulation strategy is necessary. In this work, we prepared Gemini NPs composed of drug-loaded nanoparticles DI NPs (Doxorubicin and Ibrutinib were simultaneously encapsulated by PLG-g-mPEG) and gene-loaded nanoparticles PPD NPs (pSpam1 and pshPD-L1 were simultaneously encapsulated by PEI1.8k-RT), and proposed a Gemini nanoparticles-based quadruple therapy (GNQT). Compared with triple therapy and four-drug combination therapy, GNQT demonstrated comprehensive modulation of the tumor microenvironment and had exceptional anticancer ability in melanoma model without obvious toxicity. In addition, by establishing a persistent immunological memory effect, GNQT could also successfully prevent tumor lung metastasis in mice. The GNQT proposed here provided new insights into tumor immunotherapy and had important implications for the research of preclinical antitumor immunotherapy.