Computer‐Aided Design of Self‐Assembled Nanoparticles to Enhance Cancer Chemoimmunotherapy via Dual‐Modulation Strategy

Abstract The rational design of self‐assembled compounds is crucial for the highly efficient development of carrier‐free nanomedicines. Herein, based on computer‐aided strategies, important physicochemical properties are identified to guide the rational design of self‐assembled compounds. Then, the pharmacophore hybridization strategy is used to design self‐assemble nanoparticles by preparing new chemical structures by combining pharmacophore groups of different bioactive compounds. Hydroxychloroquine is grafted with the lipophilic vitamin E succinate and then co‐assembled with bortezomib to fabricate the nanoparticle. The nanoparticle can reduce M2‐type tumor‐associated macrophages (TAMs) through lysosomal alkalization and induce immunogenic cell death (ICD) and nuclear factor‐κB (NF‐κB) inhibition in tumor cells. In mouse models, the nanoparticles induce decreased levels of M2‐type TAMs, regulatory T cells, and transforming growth factor‐β (TGF‐β), and increase the proportion of cytotoxicity T lymphocytes. Additionally, the nanoparticles reduce the secretion of Interleukin‐6 (IL‐6) by inhibiting NF‐κB and enhance the programmed death ligand‐1 (PD‐L1) checkpoint blockade therapy. The pharmacophore hybridization‐derived nanoparticle provides a dual‐modulation strategy to reprogram the tumor microenvironment, which will efficiently enhance the chemoimmunotherapy against triple‐negative breast cancer.