Shi Tang, Ling Lv, Na Liu, Xuewen Xu, Qasim Khan, Shasha Yu
Immune enhancement is a central objective in modern immunotherapy, vaccination, and regenerative medicine; however, achieving a powerful, sustained immune response while reducing overall systemic toxicity remains a major challenge. Organic biomaterials (OBs) are effective immunobioengineering platforms characterized by biocompatibility, tunable physicochemical properties, and the ability to deliver therapeutic cargo at localized, sustained doses; however, most exhibit low intrinsic immunostimulatory activity. Integrating nanoscale adjuvants into OB matrices has therefore emerged as an effective strategy to amplify immune activation by regulating immune recognition, cellular uptake, intracellular trafficking, and downstream signaling pathways. This review presents a mechanistic framework for nanoadjuvant-integrated OBs, focusing on biointerface-mediated immune sensing, complement activation, cellular internalization pathways, and antigen processing and presentation. We have summarized the major classes of natural and synthetic biomaterials, representative nanoadjuvant platforms, and key nanoengineering parameters, including particle size, surface chemistry, mechanical properties, and spatiotemporal release kinetics, that govern immune potency, polarization, and safety. Particular emphasis is placed on molecular mechanisms involving pattern recognition receptor signaling, inflammasome activation, cytokine regulation, immunometabolic reprogramming, and epigenetic remodeling of immune cells. Finally, we have discussed the translational potential of these systems for cancer immunotherapy, vaccination, regenerative medicine, and immune-inflammatory diseases, while highlighting key challenges related to immunotoxicity, biodistribution, manufacturing scalability, and regulatory translation. We have also provided mechanistic insights and rational design principles for the development of next-generation nanoadjuvant biomaterials for immune engineering.