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

Abstract

ABSTRACT 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.