Dual‐Responsive Shape‐Transformable Charge‐Reversible Nanoparticles Combined with Chemo‐Photodynamic‐Immunotherapy for the Treatment of Breast Cancer and Lung Metastasis

Abstract Herein, 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.