Inhaled Porous Microsphere with Tailored Aerodynamic Diameters and Sustained Release Behavior for Lung Cancer Treatment

ABSTRACT As the leading cause of cancer mortality with substantial healthcare costs, lung cancer demands proactive therapeutic strategies. In this study, inhalable porous microspheres were engineered to achieve chemoimmunotherapy with a favorable safety and efficacy profile for lung cancer. After optimization, the microspheres demonstrated excellent nebulization properties and prolonged lung retention due to their suitable aerodynamic and geometric diameters, making them ideal for inhalated delivery. Interestingly, the porous microspheres, once inhaled, were found to distribute broadly throughout the lungs and demonstrated resistance to clearance by macrophages. Additionally, the porous microspheres efficiently co‐encapsulated doxorubicin (Dox) and imiquimod (R837), enabling sustained pulmonary drug release. Dox‐induced immunogenic cell death synergized with R837 to elicit robust anti‐tumor immune responses. In a murine orthotopic lung cancer model, Dox&R837@MS demonstrated superior tumor suppression compared with other groups. Notably, compared to six doses of inhaled free drugs, such innovative microsphere formulation was significantly more effective in controlling tumor progression with only two doses, extending survival by >66% over a 45‐day period (0% in free drug group), while improving treatment compliance. Therefore, porous microspheres with tailored aerodynamic and geometric diameters developed in this work prove to be a promising platform for inhalation‐based drug delivery, particularly for pulmonary diseases treatment.