Inhalable multilevel responsive microspheres for radiation-induced lung injury

Radiation-induced lung injury (RILI) is a severe side effect associated with radiotherapy for thoracic tumor. RILI is a complex pathological process encompassing early-stage pneumonia and late-stage pulmonary fibrosis, and the process is irreversible. Current research predominantly focuses on early-stage radiation pneumonia, while effective therapeutic approaches for pulmonary fibrosis remain lacking. Therefore, a comprehensive therapeutic strategy addressing both pneumonia and fibrosis is urgently needed for RILI. Micro-nano carriers offer new opportunities for inhalable drug delivery to the lungs, enabling efficient transport across multiple biological barriers for the treatment of pulmonary diseases. Herein, we developed an inhalable microsphere system, RP@BDC, with multilevel responsiveness, designed to meet the size requirements for pulmonary drug delivery and to intervene the entire progression of RILI. Resveratrol and siPAI-1 were chosen as therapeutic agents to inhibit inflammation and fibrosis-related proteins. Chitosan-based nanoparticles (RP@DC) were prepared to enhance drug stability and permeability. CaCO₃ biomineralization endowed RP@BDC with acid-responsive particle size transformation properties. RP@BDC microspheres demonstrated excellent responsiveness, releasing drug-loaded nanoparticles in response to the radiation-induced acidic environment, thereby exerting therapeutic effects. In an RILI mouse model, RP@BDC effectively alleviated both radiation-induced inflammation and pulmonary fibrosis by reducing inflammatory factors production and inhibiting plasminogen activator inhibitor 1 (PAI-1) expression. Furthermore, RP@BDC exhibited superior therapeutic efficacy compared to conventional corticosteroids drug. Overall, our multilevel responsive delivery platform offers a promising therapeutic strategy for the comprehensive treatment of RILI.