Affiliation:
1. Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610064 P. R. China
2. Frontiers Medical Center Tianfu Jincheng Laboratory Chengdu Sichuan 610212 P. R. China
3. Department of Breast Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital & Institute Sichuan Cancer Center Affiliated Cancer Hospital of University of Electronic Science and Technology of China Chengdu Sichuan 610064 P. R. China
4. Mental Health Center and National Chengdu Center for Safety Evaluation of Drugs West China Hospital Sichuan University Chengdu Sichuan 610041 P. R. China
Abstract
AbstractHerein, a dual‐responsive shape‐transforming charge‐reversal integrated nanomedicine system (DHP@BPP) is developed for the co‐delivery of the photosensitizer pyro pheophorbide‐α (Ppa), anti‐programmed cell death ligand 1 (PD‐L1) peptide (dPPA), and tumor‐associated macrophages (TAMs)‐regulating drug berberrubine (BBR). Hydrophobic Ppa and hydrophilic BBR are linked by matrix metalloproteinase‐2 (MMP‐2) responsive peptide (PMGMRKLVFF) to form BPP. BPP can self‐assemble into spherical nanoparticles with positive charge, which undergo shape transformation to nanofibers upon cleavage by MMP‐2 at tumor sites. The dPPA is conjugated with hexa‐histidine and polyethylene glycol to form DHP, which is then electrostatically adsorbed onto the surface of BPP to form DHP@BPP with negative surface charge. The DHP not only enhances the tumor‐targeting but also induces DHP disassociation and charge reversal of DHP@BPP due to protonation of histidine at the tumor site, thereby increasing tumor penetration while maintaining long blood circulation. Most importantly, through the combination of chemo‐photodynamic‐immunotherapy, it can repolarize TAMs from M2‐type to M1‐type while reducing PD‐L1 expression to reshape the immunosuppressive tumor microenvironment, thereby synergistically enhancing the effect of immunogenic cell death. In conclusion, this study offered a simple but effective idea for the treatment of immunosuppressive cancers through the combination of shape transformation and charge reversal, integrating chemo‐photodynamic‐immunotherapy.
Funder
National Natural Science Foundation of China
Key Research and Development Program of Sichuan Province
Fundamental Research Funds for Central Universities of the Central South University