Bioactive nanoparticles for boosting tumor immunotherapy via Ca2+ interference mediate TME reprogramming and PD-L1 depletion

Abstract The efficacy of antitumor immunotherapy is often limited by the highly tumor immunosuppressive microenvironment (TME). Here, a previously unknown strategy is proposed to synergize the “Ca2+ interference” mediate TME reprogramming and Ca2+-activating PD-L1 depletion for immunotherapy. We discovered that calcium containing nanoparticles could induce significant “Ca2+ interference” effect and simultaneously resetting tumor-associated macrophages toward M1 phenotype and promoting in situ antigen release. Making them as powerful immunostimulants for TME reprogramming without notable toxicity. Meanwhile, we designed a circular aptamer-DNAzyme conjugate (cAD) with tumor-targeting ability and its catalytic shear activity can be specifically activated by Ca2+, which reduces potential autoimmune disorders of PD-L1 antibody. By simple integrating the ultra-high pH sensitive calcium peroxide nanoparticles with cAD into one nanosystem, we demonstrate the nanosystem not only arrests primary tumor progression, but also prevents lung metastasis. In addition, it offers a long-term immunological memory function, which can protect against tumor rechallenge. Therefore, this work provided an alternative strategy for boosting tumor immunotherapy.