Designing siRNA nanocarriers for myocardial ischemia/reperfusion injury: pathobiological targets, delivery barriers, platform strategies, and translational constraints

Аннотация

Introduction: Reperfusion remains the only effective way to salvage myocardium after acute infarction, yet restoring blood flow can itself aggravate injury through gene-regulated oxidative, inflammatory, mitochondrial, endothelial, and cell-death programs. Small interfering RNA (siRNA) can silence such transcripts with high sequence specificity, but its value in myocardial ischemia/reperfusion (MI/R) injury depends on delivery to the right cardiac cell population at the right phase of reperfusion, not on target discovery alone. This traditional narrative review builds a barrier-to-design framework for MI/R siRNA nanocarriers and is not an efficacy ranking; it was motivated by a delivery gap (the injured microvasculature can deny access to any payload) that existing platform-organized reviews leave unexamined.

Materials and Methods: Literature was screened across four domains (MI/R pathobiology and cardioprotection; RNA interference and cardiovascular RNA therapeutics; nanocarrier design for nucleic-acid delivery; preclinical cardiac nanomedicine) using structured Crossref-based searches (13 keyword groups, coverage 1982–2026, with a dedicated 2023–2026 recency pass); screening produced 152 unique candidates, of which 97 sources were retained in the evidence bank and 69 are cited, 71 % published in 2021–2026.

Results: the review reports (1) an MI/R target map governed by five explicit inclusion criteria and evidence-maturity tiers; (2) six delivery barriers, naming microvascular obstruction and endothelial permeability as the sixth, an independent access barrier added in this revision; (3) a platform-by-function analysis of lipid and lipid-hybrid, polymeric and stimulus-responsive, biomimetic and extracellular-vesicle-inspired, and inorganic, magnetic, and carbon-based carriers, including homing and local-delivery modules; (4) a comparative design map with an explicit six-tier evidence-maturity rubric (T1–T6); (5) a statement of what current evidence can and cannot support, closing with five priority directions; and (6) translational constraints, including a large-animal model-selection rationale (pig versus dog).

Conclusion: most surveyed carriers sit at early maturity tiers (T2–T3), which is the honest state of the field rather than a deficit; the next advance is more likely to come from aligning pathobiology, RNA pharmacology, and carrier engineering into one design logic than from adding new material names.

Графическая аннотация