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

Herein, a dual-responsive shape-transforming charge-reversal integrated nanomedicine system (DHP@BPP) is developed for the co-delivery of the photosensitizer pyro pheophorbide-alpha (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. This research utilizes the intrinsic properties of various drugs to design a novel pH-responsive charge-reversal, MMP-2-responsive shape-transformable, carrier-free nanoparticles, which are combined with chemo-photodynamic-immunotherapy for the treatment of breast cancer and lung metastasis. This dual-responsive nanomedicine exhibits multiple functionalities while maintaining a simple structure, enhancing tumor penetration, retention, and therapeutic efficacy through the integration of various mechanisms. image