Latent membrane protein 2 (LMP2), which is an important protein of Epstein-Barr virus (EBV) in the latent phase to mediate metastasis and recurrence, has shown great potential as a targeting antigen in mRNA vaccine for nasopharyngeal carcinoma (NPC) therapy. In this study, an LMP2 mRNA vaccine was developed based on a serum-resistant fluorinated polyethyleneimine (TKPF) with the self-adjuvant effect for achieving a strong anti-tumor immunity in NPC treatment. Specifically, the proposed vaccine PEG[TKPF/mLMP2] was comprised of a TKPF/mLMP2 core formed by the cationic TKPF and LMP2 mRNA, together with a dialdehyde poly (ethyl glycol) (OHC-PEG-CHO) coating. PEG[TKPF/mLMP2] showed less protein absorption to enable serum resistance to maintain ∼50 % transfection efficiency under 50 % FBS media. In addition, PEG[TKPF/mLMP2] could render enhanced internalization and lysosomal escape of mRNA by DC cells via positive charge and fluorine groups, followed by efficient transfection and expression, eventually triggering DC maturation and antigen presentation to T cells as demonstrated by in vitro studies. The activated antigen-specific T cells would attack tumor cells expressing LMP2 and release pro-inflammatory cytokines including IFN-γ, IL-6, and TNF-α. Furthermore, in vivo studies manifested effective spleen transfection and activated T cells by PEG[TKPF/mLMP2] to prevent tumor cell growth and prolong mouse survival in both prophylactical and therapeutical models. Notably, PEG[TKPF] revealed self-adjuvant effect to induce a strong immune response for boosting the anti-tumor potency of LMP2 mRNA. In summary, the fabricated LMP2 mRNA vaccine facilitated by the efficient and self-adjuvant vector induced robust immunotherapeutic efficacy, providing a possible solution for NPC therapy. STATEMENT OF SIGNIFICANCE: Latent membrane protein 2 (LMP2), which is a key Epstein-Barr virus (EBV) protein for metastasis and recurrence, can be targeted as an antigen for mRNA vaccine development to treat nasopharyngeal carcinoma (NPC). However, the current LMP2 vaccine is still inefficient in inducing potent anti-NPC immunity. Although mRNA has emerged as an effective tool to rejuvenate LMP2 vaccine development, it still suffers from vulnerability to serum conditions and weak immune response. In this study, we developed an LMP2 mRNA vaccine based on a serum-resistant fluorinated polyethyleneimine (TKPF) with self-adjuvant effects to achieve strong anti-tumor immunity in NPC treatment. The proposed PEG[TKPF/mLMP2] vaccine efficiently delivers to dendritic cells (DCs) for activating T cell maturation, ultimately suppressing the growth of LMP2-expressing tumors in both prophylactic and therapeutic mouse models.Copyright © 2024. Published by Elsevier Ltd.