Nanoparticle-Based Therapeutic Strategies for Pathological Cardiac Hypertrophy: Preclinical Advances, Translational Challenges, and Future Perspectives.

Pathological cardiac hypertrophy is a major contributor to heart failure and is characterized by complex molecular mechanisms involving transcriptional and epigenetic regulation, signal transduction, metabolic remodeling, inflammatory responses, and extracellular matrix remodeling. Although conventional pharmaceutical treatments may alleviate the progression of cardiac hypertrophy, their clinical effectiveness is limited by poor cardiac selectivity, systemic side effects, and limited efficacy in reverseing pathological remodeling. Recently, nanoparticle-based strategies have emerged as a promising therapeutic approach for cardiac hypertrophy owing to their ability to enhance cardiac-targeted drug delivery, enable controlled or stimuli-responsive drug release, and reduce off-target toxicity through improved biodistribution. This review systematically summarizes the design strategies of nanoparticle-based therapies for pathological cardiac hypertrophy, including material platforms such as inorganic, organic, and biomimetic nanoparticles, key delivery strategies such as passive targeting, active targeting, biomimetic targeting, and stimulus-responsive release, and administration routes including intravenous, intraperitoneal, intradermal, inhalation, and oral administration. In addition, this review provides a comprehensive summary of the preclinical applications of the above strategies in the fields of gene and epigenetic regulation, antioxidant, anti-inflammatory, and anti-fibrotic treatments. Finally, this review analyzes the challenges in clinical translation on the basis of critical issues, including long-term biosafety, insufficient targeting efficacy, large-scale production, and appropriate administration routes.