TLR agonist(Decoy Biosystems)

Clonal hematopoiesis of indeterminate potential (CHIP), driven by somatic mutations (e.g., TET2), is an independent risk factor for atherosclerosis (AS). CHIP-mutant macrophages promote plaque inflammation, but targeted therapies are lacking. Crucially, whether these clones acquire immunogenic neoantigens-enabling immune clearance-remains unexplored.

To investigate if Tet2-mutant cells in CHIP-associated AS develop immunogenic neoantigens and evaluate a neoantigen-targeting vaccine strategy.

Tet2 was edited in hematopoietic cells via CRISPR/Cas9 and transplanted into Ldlr^-/- mice fed a high-fat diet to model CHIP-accelerated AS. DNA and RNA sequencing of Tet2-mutant macrophages identified nonsynonymous mutations. Neoantigen immunogenicity was predicted in NetMHCpan. A therapeutic vaccine (GelVax) encapsulating mutant cell lysates (neoantigen source), GM-CSF (DC recruitment), and R848 (TLR agonist) within a biocompatible hydrogel was developed. Efficacy was assessed in the AS model.

Tet2 deficiency exacerbated atherosclerosis (+72% plaque area) and systemic inflammation.  DNA and RNA sequencing results identified 2 mutations showing high MHC-I binding affinity, suggesting neoantigenicity. GelVax vaccination reduced aortic plaque burden by 45%, selectively cleared Tet2-mutant macrophages in plaques, attenuated systemic cytokines (TNF-α, IL-1β) and improved plaque stability (↓ necrotic core, ↑ collagen). The protection was primarily CD8⁺ T-cell dependent.

Tet2-mutant cells in CHIP-associated AS acquire immunogenic neoantigens. Leveraging these antigens via a hydrogel vaccine induces clone-specific CD8⁺ T cell responses, clears pathogenic macrophages, and ameliorates atherosclerosis. This validates mutant neoantigens as actionable targets for CHIP-driven cardiovascular disease.

Respiratory diseases are global health challenges demanding innovative immunotherapy solutions. Toll-like receptors (TLRs) play a crucial role in immune responses, making them attractive therapeutic targets. This review examines nanoparticle-based Toll-like receptor agonists as a promising approach for respiratory immunotherapy. Nanoparticles offer targeted drug delivery and sustained release, ideal for enhancing TLR agonist efficacy. This article explores TLRs' role in immunomodulation, nanoparticle applications, design considerations, preclinical efficacy, safety assessments, challenges, and future prospects. Promising results from animal studies suggest enhanced immunological responses and reduced inflammation compared to conventional treatments. Safety concerns are addressed with insights from toxicity studies. Challenges include regulatory hurdles and biocompatibility, with strategies proposed for optimization. Nanoparticle-based TLR agonists hold great potential to transform respiratory disease treatment, warranting further research and collaboration for successful clinical translation. See also the graphical abstract(Fig. 1).