Cascade-targeted delivery platform enhances antigen cross-presentation and STING activation for durable cellular immunity.

Achieving robust and durable cellular immunity remains a key challenge in the development of subunit vaccines, primarily due to inefficient antigen cross-presentation and inadequate immune activation. Here, we engineered a series of nano-emulsions by conjugating human serum albumin (HSA) with fatty acids of varying chain lengths. Through systematic screening, the palmitic acid-modified nano-emulsion was identified as the most effective carrier, exhibiting intrinsic self-adjuvant properties and a strong capacity to elicit cellular immune responses. Notably, this formulation enables cascade-targeted delivery, trafficking sequentially from lymph nodes to antigen-presenting cells (APCs), and ultimately to the endoplasmic reticulum (ER). Upon co-delivery of the model antigen ovalbumin (OVA) and a stimulator of interferon genes (STING) agonist, the nano-emulsion facilitates both efficient antigen cross-presentation and precise intracellular activation of the STING pathway. This synergistic mechanism significantly enhances CD8+ T cell responses and promotes durable memory formation, resulting in potent antitumor efficacy in murine models. Collectively, this study presents a safe and versatile nano-emulsion platform that overcomes key barriers in subunit vaccine delivery, offering a promising strategy for next-generation vaccine design.