生物相容性和生物可降解性优异的生物高分子材料具有设计药物纳米载体的巨大潜力，但仅依靠生物高分子材料难以制造具有多种开关功能（尺寸、表面、形状）的智能载体。在此，我们报道了一种双尺寸/电荷可切换、多响应、装载多柔比星的明胶基纳米簇（DOX-icluster），用于改善肿瘤穿透和靶向抗肿瘤治疗。DOX-icluster是由叶酸和二甲基马来酰亚胺改性的明胶（FA-GelDMA）和装载小尺寸DOX的NH2修饰的中空介孔有机硅纳米粒子（DOX-HMON-NH2）静电组装而成。在中性pH下，DOX-icluster具有约199nm的初始尺寸。在肿瘤组织中积累后，FA-GelDMA的DMA键被断裂，明胶被基质金属蛋白酶（MMP-2）降解，释放出48nm和带正电荷的DOX-HMON-NH2以促进穿透和细胞内吞噬。DOX-HMON-NH2由细胞内还原型谷胱甘肽（GSH）进一步降解并释放出48.1%的DOX。细胞摄取结果表明，制造的icluster促进了DOX被4T1细胞摄取。随着穿透效能的增强，用DOX-icluster处理的肿瘤球体体积在第7天降低至15.1%。这种细胞相容性的多响应明胶基icluster具有可调整尺寸和可逆电荷特性，可能被用作重要的肿瘤治疗药物载体。 © 2023 Elsevier B.V.发表。

Biopolymers with excellent biocompatibility and biodegradability show great potential for designing drug nanocarriers, while it's difficult to fabricate smart vehicles with multiple switching (size, surface, shape) based on biopolymers alone. Here, we report a dual size/charge-switchable and multi-responsive doxorubicin-loaded gelatin-based nanocluster (DOX-icluster) for improved tumor penetration and targeted anti-tumor therapy. The DOX-icluster was electrostatically assembled from folic acid and dimethylmaleic anhydride modified gelatin (FA-GelDMA) and small-sized DOX-loaded NH2 modified hollow mesoporous organosilicon nanoparticles (DOX-HMON-NH2). DOX-icluster had an initial size of about 199 nm at neutral pH. After accumulation in tumor tissue, the DMA bond of FA-GelDMA was cleaved and gelatin was degraded by matrix metalloproteinase (MMP-2), thus 48 nm and positively charged DOX-HMON-NH2 was released to facilitate penetration and cell internalization. DOX-HMON-NH2 was further degraded by intracellular glutathione (GSH) with releasing 48.1 % of DOX. The cellular uptake results indicated that the fabricated icluster promoted the uptake of DOX by 4T1 cells. With enhanced penetration efficacy, the tumor spheroids volume treated with DOX-icluster was reduced to 15.1 % on day 7. This cytocompatible multi-responsive gelatin-based icluster with size-shrinking and charge-reversible characteristics may be used as a significant drug carrier for tumor therapy.Copyright © 2023. Published by Elsevier B.V.