Erianin-loaded biomimetic nanoadjuvant alleviates exhaustion-like CD8⁺ T-cell dysfunction and enhances radiotherapy-induced antitumor immunity

CD8⁺ T-cell exhaustion limits the efficacy of immunotherapy in solid tumors, and strategies that preserve T-cell metabolic fitness remain insufficient. Here, we found that erianin, a natural small molecule, alleviates exhaustion-like dysfunction and improves effector function in CD8 + T cells under persistent stimulatory stress, although its poor aqueous solubility and limited bioavailability restrict its therapeutic application. To improve the delivery of erianin and integrate immune-stimulatory function, we developed a biomimetic composite nanoadjuvant (PPEC), composed of a PC7A-based Polyplex core co-loaded with erianin and Poly(I: C) and coated with tumor-cell-membrane vesicles. In vitro, PPEC promoted BMDC uptake and maturation, and cytokine production consistent with an activated antigen-presenting phenotype, and preserved CD8⁺ T-cell effector activity. Comparative formulation studies further showed that the anti-exhaustion activity of the system was mainly derived from erianin. Mechanistically, erianin-associated recovery of mitochondrial function was accompanied by RXRα- associated changes in the ITPR2/MCU calcium-handling pathway and reduced mitochondria-associated Ca²⁺ accumulation. In poorly immunogenic Lewis lung carcinoma models, local administration of PPEC suppressed tumor growth, enhanced the therapeutic efficacy of radiotherapy, increased dendritic-cell maturation and CD8⁺ T-cell infiltration, and reduced selected features of intratumoral T-cell dysfunction. This work presents a mechanism-guided nanoadjuvant strategy that combines dendritic-cell activation with metabolic protection of T cells for solid tumor immunotherapy.