Postdoc Fellow Massachusetts General Hospital, Harvard Medical School Boston, Massachusetts, United States
Disclosure(s):
Shilin Gao, PhD: No financial relationships to disclose
Introduction/Rationale:
Introduction: The elderly are at a heightened risk of severe influenza due to age-related immune decline, and current vaccines provide only suboptimal protection. To address this, we targeted alveolar epithelial cells (AECs) to reprogram the aged lung microenvironment and robustly enhance vaccine efficacy.
Methods:
Methods: We developed nanoSTING@Mn, a pulmonary surfactant-biomimetic liposome encapsulating the pan-STING agonist, ADU-S100 complexed with manganese, aimed to activate the cGAS-STING pathway in AECs. Administered intranasally with inactivated fluvaccines, nanoSTING@Mn induced broad protection against divergent flu viruses after a single dose in aged mice. Comprehensive analyses, including scRNA-seq, profiling of myeloid-linage differentiations, and in vitro/in vivo functional studies, were conducted to delineate immune cell dynamics, gene expressions, and AEC-immune cell interactions in comparison with young mice.
Results:
Results: NanoSTING@Mn-adjuvanted flu vaccines offered nearly complete protection against heterosubtypic viral challenges as early as 3 days post-immunization in aged mice. The adjuvant restored aged lung immunity to youth levels by rejuvenating antigen-presenting cells (APCs) at molecular, functional, and quantitative levels while reducing Treg cells and suppressive myeloid cells. The reprogramming shifted the aged lung from an immunosuppressive toward a pro-immune state, enabling robust adaptive immune responses in aged mice.
Conclusion:
Conclusion: The study demonstrates, for the first time, that targeted activation of the cGAS–STING pathway in AECs can reverse age-associated immune dysfunction by reorienting myeloid lineage differentiation. NanoSTING@Mn thereby achieves youthful-like vaccine efficacy in aged hosts—an outcome unattainable with conventional TLR-based adjuvants. These findings offer a transformative strategy for protecting aging populations against seasonal influenza and future pandemic.
