Phenylborate-Functionalized Nanocarriers Enable Lung-Tropic Protein Delivery and Reprogramming of Tissue-Resident Immunity.

Abstract

Effective lung-targeted therapies can directly treat pulmonary diseases and engage tissue-resident immunity for lasting effects. However, protein delivery systems specifically targeting the lung remain scarce. Here, we report the discovery of phenylborate (PBA)-functionalized polymeric nanocapsules that enable efficient pulmonary delivery of protein cargos following systemic administration. Systematic structure-activity relationship studies revealed that PBA incorporation strongly correlates with enhanced lung tropism, establishing a previously unrecognized materials design principle for lung-targeted protein delivery. Leveraging this capability, we demonstrate that lung-targeted antigen delivery induces robust tissue-resident memory T cell responses within the pulmonary microenvironment and suppresses tumor growth in preclinical models of lung metastasis. Together, these findings redefine the in vivo functional role of phenylborate in nanocarrier systems and establish a versatile materials platform for lung-targeted protein therapeutics and site-specific immune modulation.