期刊
ADVANCED FUNCTIONAL MATERIALS
卷 32, 期 24, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adfm.202201275
关键词
Ca; (2+) interference; DNAzyme; PD-L1 depletion; tumor immunotherapy; tumor-associated macrophages re-education
类别
资金
- National Natural Science Foundation of China [81874304, 82093075, 31900991, U2004197, 21904119]
- Innovation Talent Support Program of Henan Province [19HASTIT006, 21HASTIT043]
- Postdoctoral Science Foundation of China [BX20200309, 2020M254785]
This study proposes a previously unknown strategy to enhance the clinical efficacy of PD-1/PD-L1 blockade by re-educating tumor-associated macrophages and depleting PD-L1 through calcium interference. The nanosystem developed in this study demonstrates the ability to inhibit tumor progression, prevent metastasis, and provide long-term immunological memory.
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.
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