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.