Engineered Macrophages Tune Intratumoral Cytokines through Precisely Controlled Self-Pyroptosis to Enhance Bladder Cancer Immunotherapy

作者：Guo, Pengyu; Dai, Peng; Yang, Shenghao; Wang, Ziqi; Tong, Zhichao; Hou, Dayong; Liu, Xiao; Xu, Wanhai^*

来源：Small, 2023.

DOI：10.1002/smll.202306699

• bladder cancer
• controlled pyroptosis
• engineered macrophages
• immunotherapy

Engineered macrophages are a promising tool for drug delivery and immunotherapy in cancer treatment. However, simultaneous targeted enrichment and controllable immunological activation of these macrophages at the tumor site remains challenging. As a solution, macrophages loaded with an advanced nanoparticle encapsulating CpG-conjugated magnetic nanoclusters (MNC) with indocyanine green (ICG) and nigericin (NIG) (MNC-ICG-NIG@SiO2 (MINS)), utilizing SeSe bond-modified SiO2, are designed and applied in bladder cancer, which is typically managed surgically, followed by Bacillus Calmette-Guerin (BCG) adjuvant instillation therapy. Upon intravenous administration, BCG-mediated tumor-localized inflammation leads to targeted accumulation of MINS@M phi. MINS@M phi accumulates within the tumor tissue and is immunologically activated through laser irradiation, leading to ICG-mediated generation of reactive oxygen species, SeSe bond cleavage, and subsequent NIG release to induce self-pyroptosis. Consequently, MINS@M phi releases Fe2+ ions and CpG, thus promoting the M1 polarization of tumor-associated macrophages and secretion of appropriate antitumor cytokines. However, without intervention, MINS@M phi undergoes apoptosis in the bloodstream after 48 h without eliciting any immune response. Therefore, this innovative approach optimizes and enhances the efficacy of BCG immunotherapy by precisely modulating the cytokines for effective bladder cancer treatment without inducing a systemic inflammatory response. @@@ Upon MINS@M phi accumulation within the tumor tissue, localized NIR irradiation is conducted. This triggers indocyanine green (ICG) to generate reactive oxygen species, disrupting SeSe bonds and rupturing the SiO2 shell, liberating nigericin (NIG). NIG induces self-pyroptosis in engineered macrophages. Additionally, it releases Fe2+ and CpG, promoting tumor-associated macrophages (TAM) polarization toward the M1 phenotype, leading to the secretion of antitumor cytokines to enhances Bacillus Calmette-Guerin (BCG) immunotherapy efficacy.image

• 单位
  中国医学科学院; 哈尔滨医科大学