The therapeutic potential of nitric oxide (NO) has been highly attractive to tumor treatment, especially for surmounting the multidrug resistance (MDR) of cancer. However, the NO-involved therapy remains extremely challenging because of the difficulty to simultaneously control the NO release rate and real-time concentration. Herein, we construct NO-containing polymersomes with high amount of NO donors inherently grown on the polymer chains to keep the stability. These polymersomes can be simultaneously loaded with photosensitizer of IR780 iodide on the membrane layer and chemotherapeutic of DOX·HCl in the lumen. NO release can be triggered by the reduction conditions, and further accelerated by remote NIR irradiation due to the increased local temperature. The instantaneous NO release with high concentration significantly inhibits the P-gp expression and sensitize the chemotherapy, thus overcoming the tumor MDR and improving the anti-tumor activity. Meanwhile, DOX·HCl release is highly promoted at the intracellular conditions because of the cleavage of acid-labile cis-aconitic amide at endo/lysosomal pH, and the improved hydrophilicity of the membrane layer after NO release. The in vivo results show that the single intravenous injection of polymersome formulation companying with NIR irradiation exerts multi-modal therapies of chemotherapy, PTT/PDT, and NO-therapy on the MCF-7/R tumor models, showing superior and combinational treatment efficacy with the complete eradication of tumors and few side effects.

一氧化氮 (NO) 的治疗潜力对肿瘤治疗非常有吸引力，尤其是对于克服癌症的多药耐药性(MDR)。然而，由于难以同时控制 NO 释放速率和实时浓度，NO 相关治疗仍然极具挑战性。在这里，我们构建了含有大量 NO 供体的含 NO 聚合物囊泡，这些 NO 供体在聚合物链上固有地生长以保持稳定性。这些聚合物囊泡可以同时装载光敏剂膜层上的 IR780 碘化物和管腔中的 DOX·HCl 化学治疗剂。NO 的释放可以由还原条件触发，并且由于局部温度升高而通过远程 NIR 辐射进一步加速。高浓度的瞬时NO释放显着抑制P-gp表达并使化疗敏感，从而克服肿瘤MDR并提高抗肿瘤活性。同时，由于内/溶酶体pH条件下酸不稳定顺乌头酰胺的裂解，以及NO释放后膜层亲水性的提高，DOX·HCl的释放在细胞内条件下得到高度促进。在体内 结果表明，单次静脉注射聚合物囊泡制剂配合近红外辐射对MCF-7/R肿瘤模型进行化疗、PTT/PDT和NO治疗的多模式治疗，显示出优越的联合治疗效果，彻底根除的肿瘤和很少的副作用。