Precision immunomodulation of viral myocarditis: a spatiotemporal intervention paradigm based on smart biomaterials

Figures

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  Figure 1. The triphasic pathophysiological cascade of viral myocarditis: from acute viral invasion to dilated cardiomyopathy. The schematic displays the tripartite progression of VMC: the initial viral phase involving direct viral lysis and PRR-mediated innate immune sensing; the subsequent immunological phase marked by adaptive immune cell infiltration and potential autoimmune cross-reactivity; and the final remodeling phase featuring progressive fibroblast activation, maladaptive fibrosis, and ventricular wall thinning. Created with Adobe Illustrator.

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  Figure 2. Innate immune sentinels and metabolic reprogramming: balancing viral clearance and collateral myocardial injury. The diagram displays: the defensive viral clearance phase, involving dsRNA recognition through the TLR3–TRIF–IRF3 cascade to drive Type I interferon and ISG production; the metabolic reprogramming phase, marked by the M1-to-M2 macrophage switch, where a transition from a glycolytic TCA cycle break (succinate stack) to intact FAO/OXPHOS shifts cytokine flow toward repair; and the maladaptive collateral injury phase, featuring persistent inflammation and cytokine storms driven simultaneously by HMGB1/TLR4 signaling and mtDNA leak-mediated cGAS–STING activation. Created with Adobe Illustrator.

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  Figure 3. Adaptive immune maladaptation: T-cell plasticity, epitope spreading, and pathogenic autoantibody production. This schematic highlights the adaptive immune dysregulation, focusing on the loss of balance between Th17 and Treg populations and the consequent T-cell plasticity. It also demonstrates the B-cell-mediated humoral response, where the release of self-antigens from damaged cardiomyocytes triggers epitope spreading and the production of functional, pathogenic autoantibodies that contribute to sustained myocardial injury. Created with Adobe Illustrator.

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  Figure 4. Cross-talk between cardiomyocyte programmed cell death and immune amplification: the role of PANoptosi:and ferroptosis. This figure illustrates the complex interplay between regulated cell death pathways and innate immune activation. It highlights how the convergence of apoptosis, pyroptosis, and necroptosis (PANoptosis) alongside ferroptosis leads to the release of DAMPs, which in turn drive the assembly of the NLRP3 inflammasome, creating a positive feedback loop of sustained inflammation and myocardial damage. Created with Adobe Illustrator.

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  Figure 5. Paradigmatic shift in therapeutic strategies: transitioning from systemic immunosuppression to bioengineered precision immunomodulation this schematic contrasts the limitations of traditional non-targeted systemic immunosuppressive therapies with emerging bioengineering strategies. It demonstrates how localized delivery platforms, such as cardiac patches, exosomes, plant-derived exosome-like nanovesicles (PELNs), biomimetic nanoparticles, and piezoelectric devices, can provide spatiotemporal regulation of the immune microenvironment, effectively suppressing pathological inflammation while preserving host antiviral capacity. Created with Adobe Illustrator.