Pulmonary delivery of immune checkpoint inhibitors (ICIs) holds promise for increasing drug concentration in the lung and reducing off-target side effects compared to systemic administration. However, the development of an ideal carrier capable of efficiently encapsulating ICIs, maintaining stability during fabrication and nebulization, and facilitating transport through the mucus barrier remains a significant challenge. Herein, we developed such a carrier by synthesizing a responsive polyethylene glycol (PEG) nanogel through crosslinking four-arm PEG via copper-free click chemistry. This approach allows for the efficient in situ encapsulation of ICIs using biocompatible PEG, eliminating the need for potentially toxic catalysts or coupling reagents. The covalently crosslinked network ensures excellent colloidal stability of nanogel during nebulization. Importantly, the PEG nanogel greatly enhances the mucus penetration and lung accumulation of free ICIs. Upon reaching the tumors, the PEG nanogel undergoes dissolution triggered by the overexpressed matrix metalloproteinase-9, leading to the release of encapsulated ICIs. We demonstrated that pulmonary delivery of PEG nanogel greatly enhanced the therapeutic efficacy of ICIs and alleviated the potential toxicity associated with intravenously injected ICIs using a lung metastasis model in mice. Overall, this work presents a simple, safe, and effective PEG nanogel platform for the pulmonary delivery of ICIs.

与全身给药相比，免疫检查点抑制剂（ICIs）的肺部给药有望增加肺部药物浓度并减少脱靶副作用。然而，开发一种能够有效封装 ICI、在制造和雾化过程中保持稳定性以及促进通过粘液屏障运输的理想载体仍然是一个重大挑战。在这里，我们通过合成响应性聚乙二醇开发了这样的载体(PEG) 纳米凝胶通过无铜点击化学交联四臂 PEG。这种方法可以使用生物相容性 PEG 有效地原位封装 ICI，从而无需使用潜在有毒的催化剂或偶联试剂。共价交联网络确保纳米凝胶在雾化过程中具有优异的胶体稳定性。重要的是，PEG 纳米凝胶极大地增强了游离 ICI 的粘液渗透和肺部积聚。到达肿瘤后，PEG 纳米凝胶会在过表达的基质金属蛋白酶 9 的作用下发生溶解，导致封装的 ICI 释放。我们在小鼠肺转移模型中证明，PEG 纳米凝胶的肺部递送极大地增强了 ICI 的治疗效果，并减轻了与静脉注射 ICI 相关的潜在毒性。