Boosting Tumor Immunotherapy by Bioactive Nanoparticles via Ca2+ Interference Mediated TME Reprogramming and Specific PD-L1 Depletion

The clinical outcomes of programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) blockade are usually limited by the multiple immune evasion mechanism of the tumor, as well as the immune storm caused by "off-target" effects of the PD-1/PD-L1 antibody. Here, a previously unknown strategy is proposed to synergize the "Ca2+ interference" mediated M2-like tumor-associated macrophages (TAM) re-education and Ca2+-activating locally PD-L1 depletion for immunotherapy. The authors discover that calcium-containing nanoparticles can induce significant "Ca2+ interference" effect and simultaneously reset TAM toward the M1 phenotype through activation of multiple inflammation-related signaling pathways, as well as NLRP3 inflammasomes, and promoting in situ tumor-associated antigen release. In addition, a circular aptamer-DNAzyme conjugate (cAD) is designed with a tumor-targeting ability and its catalytic shear activity can be specifically activated by Ca2+, which reduces potential autoimmune-like disorders of PD-L1 antibody. By simply integrating the ultra-high pH-sensitive calcium peroxide nanoparticles with cAD into one nanosystem, it is demonstrated that the nanosystem not only arrest primary tumor progression and lung metastasis but also provides a long-term immunological memory, which can protect against tumor rechallenge. Therefore, this work provides an attractive strategy for boosting tumor immunotherapy.