Accurate tumor targeting, deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine. To achieve these requirements, a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer (d-SN38)-loaded nanoparticles (d-SN38@NPs/iRGD). Upon intravenous injection, d-SN38@NPs with high drug loading efficiency (33.92 ± 1.33%) could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD. The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy. The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm, which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor. In vitro, co-administering iRGD with d-SN38@NPs+laser showed higher cellular uptake, apoptosis ratio and multicellular spheroid penetration. In vivo, d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor, leading to 60.89% of tumor suppression in 4T1 tumor-bearing mouse model with a favorable toxicity profile. Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting, penetrating and retention, and empowers anticancer efficacy.

精确的肿瘤靶向，深层渗透和出色的保留仍然是开发出色的纳米药物的主要追求。为了达到这些要求，通过将肿瘤渗透肽iRGD与可变形和GSH响应的SN38-二聚体（d-SN38）负载的纳米颗粒（d-SN38 @ NPs / iRGD）并用，开发了逐步刺激响应策略。静脉注射后，在iRGD的​​辅助下，高载药效率（33.92±1.33％）的d-SN38 @ NPs可以有效地积累并渗透到肿瘤部位的深处。聚集的纳米粒子在肿瘤部位经650 nm激光辐照后同时转变为纳米纤维，从而促进其在肿瘤中的滞留和活性氧的爆炸释放，以进行光动力治疗。在体外，将iRGD与d-SN38 @ NPs +激光共同给药显示更高的细胞摄取，细胞凋亡率和多细胞球体渗透。在体内，d-SN38 @ NPs / iRGD +激光在肿瘤中显示出先进的渗透和积累，从而在具有有利毒性的4T1荷瘤小鼠模型中导致60.89％的肿瘤抑制。我们的新策略将iRGD与可转化结构的纳米粒子相结合，大大改善了肿瘤靶向性，穿透性和保留能力，并赋予了抗癌功效。