Deciphering the immunomodulatory code: how metal nanoadjuvants orchestrate intracellular immune signaling cascades

While aluminum salts remain the most widely applied vaccine adjuvants, other metals, such as manganese, calcium, zinc, iron and gold, have demonstrated remarkable capacity to potentiate both innate and adaptive immune responses to vaccine antigens. Moreover, nanoparticles can potentiate the immunomodulatory properties of metals through improving antigen delivery and intercellular communication among immune cells, uncovering the superior adjuvanticity of metal nanoparticles. Importantly, emerging evidence has revealed that metal nanoadjuvants tune intracellular signaling cascades including NLRP3 inflammasome, STING pathway, Toll-like receptors (TLRs), ferroptosis, autophagy, pyroptosis, metabolic regulation, and immunogenic cell death (ICD), to enhance cellular and humoral immune responses. Meanwhile, the in silico docking investigations have uncovered the potential interaction between metal adjuvants and immune-related proteins. However, the mechanistic insights into metal nanoadjuvant-mediated signal transduction in immune cells remain poorly understood. Furthermore, critical factors such as particle size, shape, surface charge, dosage and route of administration significantly influence the potency of metal nanoadjuvants, and their clinical translations highly depend on continued in-depth efforts in material engineering, mechanistic elucidation, and efficacy evaluation. This review systematically summarizes and discusses the immunomodulatory signaling mechanisms and functions associated with metal nanoadjuvants in vaccine and immunotherapy, providing a versatile platform for metal-based nanoparticles as next-generation adjuvant candidates with extraordinary immunostimulatory potentials.