The chemotherapy combined with photothermal therapy has been a favorable approach for the treatment of breast cancer. In present study, nanoparticles with the characteristics of photothermal/matrix metalloproteinase-2 (MMP-2) dual-responsive, tumor targeting, and size-variability were designed for enhancing the antitumor efficacy and achieving “on-demand” drug release markedly. Based on the thermal sensitivity of gelatin, we designed a size-variable gelatin nanoparticle (GNP) to encapsulate indocyanine green (ICG) and doxorubicin (DOX). Under an 808 nm laser irradiation, GNP-DOX/ICG responded photothermally and swelled in size from 71.58 ± 4.28 to 160.80 ± 9.51 nm, which was beneficial for particle retention in the tumor sites and release of the loaded therapeutics. Additionally, GNP-DOX/ICG showed a size reduction of the particles to 33.24 ± 4.11 nm and further improved drug release with the degradation of overexpressed MMP-2 in tumor. In the subsequently performed in vitro experiments, it was confirmed that GNP-DOX/ICG could provide a therapeutic effect that was enhanced and synergistic. Consequently, GNP-DOX/ICG could efficiently suppress the growth of 4T1 tumor in vivo. In conclusion, this study may provide a promising strategy in the rational design of drug delivery nanosystems based on gelatin for chemo-photothermal therapy to achieve synergistically enhanced therapeutic efficacy against breast cancer.

化疗联合光热疗法已成为治疗乳腺癌的有利方法。在本研究中，设计了具有光热/基质金属蛋白酶-2（MMP-2）双响应、肿瘤靶向和尺寸可变特性的纳米颗粒，以增强抗肿瘤功效并显着实现“按需”药物释放。基于明胶的热敏感性，我们设计了一种尺寸可变的明胶纳米颗粒（GNP）来封装吲哚菁绿（ICG）和阿霉素（DOX）。在 808 nm 激光照射下，GNP-DOX/ICG 发生光热反应，尺寸从 71.58 ± 4.28 膨胀至 160.80 ± 9.51 nm，这有利于颗粒在肿瘤部位的保留和负载治疗药物的释放。此外，GNP-DOX/ICG 显示颗粒尺寸减小至 33.24 ± 4.11 nm，并通过降解肿瘤中过表达的 MMP-2 进一步改善药物释放。在随后进行的体外实验中，证实GNP-DOX/ICG可以提供增强且协同的治疗效果。因此，GNP-DOX/ICG可以有效抑制体内4T1肿瘤的生长。总之，这项研究可能为合理设计基于明胶的化学光热疗法药物递送纳米系统提供有前景的策略，以实现协同增强乳腺癌的治疗功效。