The restricted tumor penetration has been regarded as the Achilles' Heels of most nanomedicines, largely limiting their efficacy. To address this challenge, a cluster-bomb-like nanoplatform named CPIM is prepared, which for the first time combines size-transforming and transcytosis strategies, thus enhancing both passive and active transport. For passive diffusion, the “cluster-bomb” CPIM (135 nm) releases drug-loaded “bomblets” (IR780/1-methyl-tryptophan (1 MT) loaded PAMAM, <10 nm) in response to the high reactive-oxygen-species (ROS) concentration in tumor microenvironment (TME), which promotes intratumoral diffusion. Besides, IR780 generates ROS upon NIR irradiation and intensifies this responsiveness; therefore, there exists a NIR-triggered self-destructive behavior, rendering CPIM spatiotemporal controllability. For active transport, the nanoplatform is proven to be delivered via transcytosis with/without NIR irradiation. Regarding the anti-cancer performance, CPIM strengthens the photodynamic therapy (PDT)/photothermal therapy (PTT) activity of IR780 and IDO pathway inhibition effect of 1 MT, thus exhibiting a strongest inhibitory effect on primary tumor. CPIM also optimally induces immunogenic cell death, reverses the “cold” TME to a “hot” one and evokes systemic immune response, thus exerting an abscopal and anti-metastasis effects. In conclusion, this work provides a facile, simple yet effective strategy to enhance the tumor penetration, tumor-killing effect and antitumor immunity of nanomedicines.

受限的肿瘤穿透被认为是大多数纳米药物的致命弱点，很大程度上限制了它们的疗效。为了应对这一挑战，我们制备了一种名为 CPIM 的类似集束炸弹的纳米平台，它首次结合了尺寸转换和转胞吞作用策略，从而增强被动和主动运输。对于被动扩散，“簇炸弹”CPIM（135 nm）响应高活性氧释放载药“炸弹”（IR780/1-甲基色氨酸（1 MT）负载 PAMAM，<10 nm）。肿瘤微环境 (TME) 中的物种 (ROS) 浓度，促进肿瘤内扩散。此外，IR780 在 NIR 照射下会产生 ROS 并增强这种反应性；因此，存在 NIR 触发的自毁行为，从而呈现 CPIM 时空可控性。对于主动运输，纳米平台已被证明可通过转胞吞作用（有/无 NIR 照射）递送。在抗癌性能方面，CPIM增强了光动力IR780的治疗（PDT）/光热治疗（PTT）活性和1 MT的IDO途径抑制作用，因此对原发性肿瘤表现出最强的抑制作用。CPIM 还可以最佳地诱导免疫原性细胞死亡，将“冷”TME 转变为“热”TME，并引发全身免疫反应，从而发挥异位和抗转移作用。总之，这项工作为增强纳米药物的肿瘤穿透、肿瘤杀伤作用和抗肿瘤免疫提供了一种简便有效的策略。