Advances and Translational Challenges in mRNA–Lipid Nanoparticle Vaccines Against Helicobacter pylori: From Rational Antigen Design to Mucosal Immunity

Helicobacter pylori chronically infects more than half of the global population and is the sole bacterium classified as a Group 1 carcinogen by the International Agency for Research on Cancer. Despite decades of effort, no prophylactic H. pylori vaccine has reached the market, largely because conventional subunit and whole-cell candidates failed to induce durable, mucosa-protective T-helper 1 (Th1)/Th17 immunity in humans. The clinical success of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA–lipid nanoparticle (mRNA-LNP) vaccines has re-energized nucleic-acid vaccine research and provided a validated, scalable delivery platform. This review synthesizes the emerging mechanistic rationale and early preclinical evidence evaluating whether mRNA-LNP technology can address key bottlenecks in H. pylori vaccine development: cytoplasmic antigen expression naturally favors major histocompatibility complex (MHC) class I/II presentation and CD8⁺/Th1 responses (notably, recent human and murine evidence demonstrates that cytotoxin-associated gene A [CagA]-specific gastric CD8⁺ tissue-resident memory T [TRM] cells control early H. pylori infection), multi-antigen and conserved-epitope designs can be generated rapidly by reverse vaccinology, and the LNP carrier itself acts as an intrinsic innate immune adjuvant. We summarize the principal candidate antigens (urease subunit B [UreB], CagA, vacuolating cytotoxin A [VacA], neutrophil-activating protein [NAP], H. pylori adhesin A [HpaA], and γ-glutamyl transpeptidase [GGT]), dissect LNP composition and intracellular trafficking, and critically appraise the nascent body of preclinical H. pylori mRNA and nanocarrier studies published between 2021 and 2026—specifically distinguishing two recent in vivo mRNA-LNP preprints (encoding full-length UreB or UreB₁₉₉–₃₃₈ cytokine/immunoglobulin Z [IgZ] fusions) from peer-reviewed in silico multi-epitope mRNA and self-amplifying RNA (saRNA) designs, LNP-adjuvanted recombinant UreB/NapA protein vaccines, all-trans retinoic acid-loaded gut-tropic nanovaccines, and oral/lipid DNA vaccine benchmarks. We also reconcile classic evidence that bacterial clearance can proceed in B-cell-deficient mice via MHC class II-restricted CD4⁺ T cells with the ancillary role of functional adhesion- and urease-blocking antibodies, and we examine critical safety and immunopathological constraints—including post-immunization gastritis, oncogenic CagA EPIYA motif detoxification, and target-population stratification (uninfected children versus infected adults). We conclude that while mRNA-LNP represents a promising exploratory modality for an H. pylori vaccine, the current experimental evidence base remains narrow and preliminary; peer-reviewed validation of in vivo Th17 induction, antigen breadth, mucosal delivery route, and long-term durability in non-human primate and human challenge models will be required to establish clinical feasibility.