The first generation of nanomedicine exhibits superior performance in the clinical treatment of various cancers compared to free conventional anticancer therapeutics. However, poor tumor penetration has been considered a major obstacle in the cancer treatment process and substantially impairs the overall therapeutic efficacy. Recently, this situation has been effectively improved through a great variety of smart size-shrinkable drug delivery nanosystems (SSDDNs), which remains stable with relatively large size in the circulation system for a prolonged plasma half-life and enhanced tumor accumulation, then specifically turn into smaller particles at the tumor site by an appropriate stimulus to promote tumor penetration for uniform drug distribution throughout the whole tumor. In this review, we systematically summarize the intelligent size-shrinkable strategies mediated by different response modes, including endogenous and external stimuli. In addition to offering enhanced penetration, the size-shrinkable strategy can companion imaging probes for specific diagnoses and image-guided therapy. The challenges and prospects are discussed, and several proposals for promoting SSDDNs clinical translation are supplied. It is anticipated that such smart SSDDNs will provide a guideline for next-generation clinical translation.

中文翻译：

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获得双方优势：智能尺寸可收缩药物输送纳米系统，实现高积累和深度渗透

与免费的传统抗癌疗法相比，第一代纳米药物在各种癌症的临床治疗中表现出优越的性能。然而，肿瘤渗透性差被认为是癌症治疗过程中的主要障碍，并严重损害了整体治疗效果。最近，通过多种智能尺寸可收缩药物递送纳米系统（SSDDN）有效改善了这种情况，SSDDN在循环系统中保持相对较大的尺寸稳定，从而延长血浆半衰期并增强肿瘤蓄积，然后具体将通过适当的刺激，在肿瘤部位分解成更小的颗粒，以促进肿瘤渗透，使药物均匀分布在整个肿瘤中。在这篇综述中，我们系统地总结了由不同反应模式（包括内源性和外部刺激）介导的智能尺寸缩小策略。除了提供增强的穿透力之外，尺寸缩小的策略还可以与成像探针配合进行特定诊断和图像引导治疗。讨论了挑战和前景，并提出了促进 SSDDN 临床转化的若干建议。预计这种智能 SSDDN 将为下一代临床翻译提供指南。