通过应用外源刺激刺激较大纳米粒子 (NP) 的释放，有可能解决阻碍化疗药物输送的循环与渗透的不同尺寸要求。在此，我们报告了一种基于尺寸切换纳米组装的药物递送系统，该系统由封装在聚（低聚（乙二醇）甲醚甲基丙烯酸酯）纳米凝胶（POEGMA，～ 150 nm 主要尺寸）通过超分子 PEG/α-环糊精 (α-CD) 相互作用进行交联。使用非侵入性高强度聚焦超声 (HIFU) 触发器加热纳米凝胶后，热响应性 POEGMA-CD 纳米组件局部去交联，诱导高渗透性载药 SNP 的原位释放。 3 小时后，HIFU 触发将纳米组件负载的 DOX 的释放从 17% 增加到 37%，这一结果与在没有 HIFU 或单独药物的情况下相对于纳米组件而言显着更有效的肿瘤杀伤作用相关。此外，当用荧光团标记的 SNP 制备的纳米组件被 HIFU 触发时，相对于没有 HIFU 的情况，在肿瘤球体内观察到的总荧光增加了 1.5 倍。我们预计该策略有望使用非侵入性触发方法在肿瘤部位和肿瘤部位内提供可调剂量的化疗药物。

Stimulating the release of small nanoparticles (NPs) from a larger NP via the application of an exogenous stimulus offers the potential to address the different size requirements for circulation versus penetration that hinder chemotherapeutic drug delivery. Herein, we report a size-switching nanoassembly-based drug delivery system comprised of ultrasmall starch nanoparticles (SNPs, ∼20-50 nm major size fraction) encapsulated in a poly(oligo(ethylene glycol) methyl ether methacrylate) nanogel (POEGMA, ∼150 nm major size fraction) cross-linked via supramolecular PEG/α-cyclodextrin (α-CD) interactions. Upon heating the nanogel using a non-invasive, high-intensity focused ultrasound (HIFU) trigger, the thermoresponsive POEGMA-CD nanoassemblies are locally de-cross-linked, inducing in situ release of the highly penetrative drug-loaded SNPs. HIFU triggering increased the release of nanoassembly-loaded DOX from 17 to 37% after 3 h, a result correlated with significantly more effective tumor killing relative to nanoassemblies in the absence of HIFU or drug alone. Furthermore, 1.5× more total fluorescence was observed inside a tumor spheroid when nanoassemblies prepared with fluorophore-labeled SNPs were triggered with HIFU relative to the absence of HIFU. We anticipate this strategy holds promise for delivering tunable doses of chemotherapeutic drugs both at and within a tumor site using a non-invasive triggering approach.