TABLE 5.

Platform-specific safety and translational considerations.

Platform/risk domain	Current evidence signal	Main unresolved limitation	Translational implication	Refs
General systemic safety	Selected studies report no obvious toxicity, preserved organ function, or lower toxicity than systemic/free drug	Non-standardized toxicology; limited repeated-dose and chronic assessment	Supports preliminary tolerability only	(Fu et al., 2026; Ji et al., 2023; Lee et al., 2015)
Systemic targeted nanoparticles	Myocardial enrichment, reduced off-target sequestration, imaging and PK gains	Whole-organ biodistribution, clearance, dose proportionality, repeat dosing	Potential acute/peri-reperfusion applicability if PK and safety mature	(Li et al., 2026; Ma et al., 2025b; Wang et al., 2025c; Zhang et al., 2016)
Local hydrogels/patches	High myocardial retention, prolonged release, responsive degradation	Invasive administration, residual material, local toxicity, degradation products	Strong local-control potential but procedure-dependent applicability	(Ding et al., 2020; Tan et al., 2024; Vong et al., 2018; Wang et al., 2022)
Metal/inorganic nanozymes	Sustained catalytic activity and cardiac efficacy	Persistence, ion release, transformation, chronic deposition	Catalytic durability is both an advantage and a safety burden	(Fu et al., 2026; Gong et al., 2025; Wang et al., 2025c; Xu et al., 2026; Zhu et al., 2025)
Cells/biological carriers	Improved cell or vesicle retention and localized biological activity	Immunogenicity, graft persistence, arrhythmogenicity, source/batch variability	Higher regulatory and manufacturing complexity	(Cao et al., 2026; Ding et al., 2022; Liu et al., 2026a; Liu et al., 2023; Shiekh et al., 2022)
Nucleic-acid systems	miRNA, siRNA, or plasmid delivery broadens mechanism	Off-target regulation, innate immunity, duration and reversibility	Requires gene-therapy-specific safety characterization	(Chen et al., 2025b; Hu et al., 2026; Liao et al., 2025; Wang et al., 2025b)
NO/CO/H2S platforms	Local or targeted redox-gas delivery with therapeutic benefit	Dose-release control, systemic exposure, hemodynamic effects	High potential but narrow safety-control requirements	(Hao et al., 2022; Vong et al., 2018; Wang et al., 2026; Wang et al., 2025e; Wu et al., 2025a)
Large-animal/clinical maturity	One explicitly identified porcine MI study with 50-day follow-up	Sparse replication; no human evidence identified	Advanced preclinical signal, not clinical readiness	(Wang et al., 2025b)
Manufacturing readiness	Selected systems show rapid gelation, simple formulation, reproducibility, or proposed scalability	GMP scale-up, sterilization, stability, QC, potency, cost, and classification largely unreported	Manufacturing may limit highly multifunctional systems	(Ding et al., 2020; Huang et al., 2022; Luo et al., 2025b; Tan et al., 2024)