IF a lipid nanoparticle (LNP)-encapsulated bivalent mRNA vaccine encoding the extracellular domains of both GPNMB and DPP4 (each as separate open reading frames within a single LNP formulation, ~1 µg total mRNA/dose, intramuscular injection, three-dose prime-boost-boost protocol at weeks 0, 3, and 6) is administered to 18-month-old male and female C57BL/6J mice (physiologically aged, with established senescent cell burden),

THEN the vaccinated animals will show: (1) ≥40% reduction in GPNMB⁺DPP4⁺ senescent cell frequency in visceral adipose tissue (VAT), liver, and aortic plaques as quantified by flow cytometry and p16^INK4a/p21 co-immunostaining at 12 weeks post-final boost; (2) measurable induction of both antigen-specific IgG antibodies (serum ELISA) and cytotoxic CD8⁺ T cells (intracellular cytokine staining for IFN-γ/granzyme B upon ex vivo restimulation); (3) reduction in circulating SASP markers (IL-6, MMP-3, PAI-1) by ≥30%; and (4) improvement in grip strength, glucose tolerance (GTT), and rotarod performance versus age-matched PBS controls,

BECAUSE the following mechanistic chain is engaged:

1. Systemically accumulated GPNMB⁺ and DPP4⁺ senescent cells drive chronic tissue inflammation and functional decline through their SASP; preclinical transcriptomic profiling identified GPNMB as a robust surface antigen upregulated on senescent cells across VAT, aorta, and progeroid tissues (literature summary, Yoshida/Suda et al., Nature Aging), while DPP4/CD26 is independently induced and surface-enriched on senescent human cells confirmed by mass spectrometry of membrane proteomes (DPP4 senescent surface marker identification)[https://doi.org/10.1101/gad.302570.117].

2. LNP-mRNA delivery to antigen-presenting cells (APCs) drives high-level intracellular translation of GPNMB and DPP4 extracellular domain antigens, eliciting simultaneous MHC class I (CD8⁺ CTL) and MHC class II (CD4⁺ T helper / antibody) adaptive responses; the LNP itself acts as an intrinsic adjuvant by stimulating innate pattern recognition, partially overcoming age-related immunosenescence that would blunt peptide vaccine responses.

3. Vaccine-induced IgG antibodies against surface GPNMB and DPP4 opsonize senescent cells; critically, antibody Fc engagement with Fcγ receptors (FcγRIII/CD16) on NK cells triggers antibody-dependent cellular cytotoxicity (ADCC), which has been directly validated as an effective kill mechanism for DPP4-positive senescent cells — DPP4-targeting antibodies selectively eliminated DPP4⁺ senescent cells via ADCC in proof-of-concept experiments (ADCC-mediated senescent cell elimination)[https://doi.org/10.1101/gad.302570.117].

4. Dual-antigen targeting reduces the probability of antigen-negative immune escape: a senescent cell that downregulates GPNMB remains targetable via DPP4, and vice versa, an escape mechanism that single-antigen approaches cannot prevent [SPECULATIVE but supported by analogous antigen-escape literature in oncology].

5. Vaccine-...

SENS category: GlycoSENS

Key references: • doi.org/10.1101/gad.302570.117]. • doi.org/10.1111/acel.12234]. • doi.org/10.1111/acel.12545]. • doi.org/10.1101/gad.302570.117]; • doi.org/10.1101/gad.302570.117],