A Noninvasive and Highly Effective Inhaled Nanovaccine Based on Natural Polysaccharide for Lung Cancer Treatment

Abstract Lung cancer is the most widespread malignancy globally and the leading cause of cancer‐related deaths, highlighting the need for innovative treatments. Herein, a novel inhaled vaccine carrier is presented by modifying dextran (Dex) with N , N ‐dimethylethylenediamine (DMEN) and 4‐(bromomethyl)phenylboronic acid (PBA) (Dex–DMEN–PBA, DDP). The optimized DDP demonstrates a potent adjuvant effect in promoting dendritic cell (DC) maturation by multiple signaling pathways. Moreover, the nanovaccine (DDP/Lewis lung carcinoma (LLC)) forms through electrostatic interactions between DDP and protein antigens derived from LLC cells. Upon inhalation, it induces DC maturation, T cell activation, and germinal center B cell activation in the thoracic lymph node. In the mouse model, the inhaled DDP/LLC nanovaccine displays impressive prophylactic effects against lung cancer, with 50% of mice alive after six months and 33% surviving a subsequent challenge, indicating strong long‐term immune memory. Remarkably, it surpasses subcutaneous vaccination, particularly in activating germinal center B cells and follicular helper T (Tfh) cells, and upregulating tissue‐resident memory T (T RM ) cells in the lung. This self‐adjuvant nanovaccine effectively prevents tumor growth and induces robust immune memory, offering valuable insight for treating lung cancer and related diseases.