Luo, J.Wang, Y.Dai, Z.Shi, Y.Wu, W.Qu, J.Zhong, Y.Xian, J.Yu, C.Yang, Y.2025-10-212025-10-212025Small, 2025; 21(42):e05250-1-e05250-141613-68101613-6829https://hdl.handle.net/2440/147907First published: 26 August 2025The efficacy of cancer vaccines depends significantly on adjuvants that can stimulate robust Th1 immune responses. However, conventional inorganic adjuvants like Alum generally elicit Th2-biased immune response. Despite recent efforts in developing organic adjuvants to mimic bacterial or viral infections for generating Th1 immunity, excessive inflammation remains a major concern. Herein, a new class of Th1-biased adjuvant is reported via passivation engineering of zinc peroxide nanoparticles (p-ZPNs) for potentiating the immunogenicity of cancer vaccines. p-ZPNs show improved biocompatibility compared to unpassivated ZPNs due to retarded zinc ion release and hydrogen peroxide production, as well as efficient cellular uptake, endosome escape, dendritic cell maturation and antigen cross presentation. Mechanistic study indicates the intrinsic activity of p-ZPNs to activate toll-like receptors (TLR)-2, 4, and 6, triggering the TLR/Myeloid differentiation primary response 88 (MyD88)/Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) axis for producing proinflammatory cytokines and therefore a robust Th1 immunity. Biosafety evaluation has shown the importance of the passivation engineering of ZPNs in reducing safety risks. Furthermore, in a p-ZPNs-based autologous cancer vaccine model, potent immune response is demonstrated in the inhibition of B16F10 tumors in both prophylactic and therapeutic vaccination settings. These findings suggest the great potential of p-ZPN adjuvants for future Th1-biased vaccine development.en© 2025 The Author(s). Small published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.cancer vaccineimmunotherapynano‐adjuvantTh1 immunityzinc peroxideJournal article10.1002/smll.202505250858637Shi, Y. [0000-0001-9734-6574]Yang, Y. [0000-0001-6696-3879]