Rapid drift of the SARS‑CoV‑2 evolutionary tensor and the collapse of neutralization thresholds for existing vaccines. Since the JN.1 lineage, the virus has continuously evaded host immunity by accumulating amino‑acid point mutations within the spike protein receptor‑binding domain (RBD), exemplified by variants such as FLiRT (KP.2, KP.3) and FLuQE (KP.3.1.1). The newly emergent Omicron XEC subvariant has further refined its three‑dimensional topology through computational genomic recombination among distinct lineages. This structural diversification has completely nullified the humoral sensitivity induced by conventional monovalent or bivalent mRNA vaccine guidelines, driving neutralizing antibody titers (NT_50) below baseline and creating a critical technical bottleneck and surveillance blind spot.

XEC‑targeted mRNA‑LNP architecture: structure‑guided reverse‑engineering virtual screening and antigen encoding. To neutralize this genetic selective pressure and construct an antigenic moat, we deployed a next‑generation mRNA‑LNP platform that precisely encodes the Omicron XEC spike genome. By analyzing the N‑terminal domain (NTD) and RBD structural features of the XEC variant, we synthesized codon‑optimized sequences that offset the free‑energy gain of ACE2 binding and mapped them at high resolution onto the mRNA backbone. This programmable nucleic‑acid payload was packaged into a next‑generation lipid nanoparticle engineered to avoid hepatic sequestration, enhance lymph‑node trafficking, and accelerate APC internalization, thereby preserving in‑vivo stability and antigen‑expression velocity.

Heterologous KP.3 strain cross‑protection demonstrated in transgenic mouse challenge studies. In hACE2 transgenic mice, the XEC‑S‑mRNA vaccine induced strong, durable cellular immunity (T‑cell responses) together with a broad neutralizing antibody repertoire that spanned both early and recent Omicron sublineages. Passive transfer of vaccine‑elicited antibody pools into naïve recipients completely clamped viral replication kinetics and conferred protection against lethal challenge with the structurally distinct Omicron KP.3 variant, quantitatively confirming universal defensive efficacy of the antibody‑only payload.

Establishment of a universal variant‑responsive vaccine standard and commercialization of the in silico nucleic‑acid design platform. The structural immunology and nucleic‑acid delivery dataset generated herein constitutes a disruptive asset for global next‑generation biopharma R&D and vaccine engineering. By shifting variant‑responsive vaccine development from reactive sequence swaps to a proactive in silico epitope synthesis platform that predicts three‑dimensional evolutionary trajectories of circulating strains and pre‑emptively filters downstream variants, we have reset the paradigm. The derived neutralization‑weight matrix will serve as a master reference for real‑time computational screening engines that instantly reprogram mRNA sequences upon emergence of novel recombinant variants, thereby pre‑calculating clinical trial throughput thresholds and dramatically shortening regulatory approval timelines for variant‑matched therapeutics.