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.

中文翻译：

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双响应形状可转变电荷可逆纳米粒子联合化疗-光动力-免疫疗法治疗乳腺癌和肺转移


在此，开发了一种双响应形状转换电荷反转集成纳米医学系统（DHP@BPP），用于共同递送光敏剂焦脱镁叶绿酸-α（Ppa）和抗程序性细胞死亡配体1（PD-L1）肽（dPPA）和肿瘤相关巨噬细胞（TAM）调节药物小檗红素（BBR）。疏水性 Ppa 和亲水性 BBR 通过基质金属蛋白酶 2 (MMP-2) 响应肽 (PMGMRKLVFF) 连接形成 BPP。 BPP可以自组装成带正电荷的球形纳米粒子，在肿瘤部位被MMP-2裂解后形状转变为纳米纤维。 dPPA与六组氨酸和聚乙二醇缀合形成DHP，然后静电吸附到BPP表面，形成表面带负电荷的DHP@BPP。 DHP不仅增强了肿瘤靶向性，而且由于组氨酸在肿瘤部位的质子化，诱导DHP解离和DHP@BPP的电荷反转，从而增加肿瘤渗透性，同时维持长时间的血液循环。最重要的是，通过化疗-光动力-免疫疗法的结合，可以将TAM从M2型复极化为M1型，同时减少PD-L1表达，重塑免疫抑制性肿瘤微环境，从而协同增强免疫原性细胞死亡的效果。总之，本研究通过结合形状转变和电荷反转，整合化学-光动力-免疫疗法，为免疫抑制性癌症的治疗提供了一种简单而有效的思路。