Pulmonary delivery of immune checkpoint inhibitors using a responsive polyethylene glycol nanogel for treating lung metastasis

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.