Inhalable Respiratory Driven Penetration of Porous Microsphere‐Based Mucosal Vaccine for Long‐Term Immune Protection

Inhalable mucosal vaccines elicit mucosal immunity non-invasively but are hindered by lung barriers like mucociliary clearance and phagocytosis, which typically necessitate multiple doses. Herein, we developed an innovative inhalable porous microsphere (pMS) vaccine using a single Food and Drug Administration-approved material, featuring a dual-scale design: an aerodynamic diameter of 4.84 µm for optimal deep lung deposition and a geometric size of 14.7 µm to evade phagocytosis for long-term retention. Notably, respiratory motion facilitates the penetration of pMS through the mucus layer into the pulmonary interstitium, where it gradually releases antigens and adjuvants. Remarkably, a single inhalation induced durable immunity, sustaining high levels of IgG and IgA for one year, alongside enhancing tissue-resident memory T cells in the lung and promoting germinal center expansion in the lymph node. This provided long-term protective efficacy, significantly inhibiting lung tumor metastasis even a year after inhalation. Beyond prophylaxis, this vaccine demonstrated remarkable therapeutic efficacy across multiple preclinical models, including the in situ lung tumor model, postoperative recurrence prevention model, and clinically relevant Patient-Derived tumor Xenograft (PDX) model. The dry powder pMS platform is scalable, stable, and clinically translatable, emerging as a versatile therapeutic strategy to adapt to diverse Lung-related diseases.