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

Figures

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  Figure 1. Etiology of pathological cardiac hypertrophy and the therapeutic potential of nanoparticle-based treatments (created with BioRender.com). Cardiac hypertrophy arises from diverse stimuli such as pressure overload, neurohumoral activation, and genetic mutations and can progress to heart failure. Traditional treatments offer low cost and an established safety profile but are limited by side effects and inadequate reversal of hypertrophy. Nanoparticle-based treatments enable targeted delivery, stimuli-responsive release, and potential reversal of remodeling, but their high cost and preclinical status remain major translational hurdles.

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  Figure 2. Theoretical schematic of nanoparticle-based controlled drug release and its potential impact on therapeutic efficacy and safety (created with BioRender.com). This is an idealized conceptual model of controlled drug release using nanoparticles. Compared with free drugs, which show rapid release and a sharp peak in plasma drug concentration followed by rapid decline, nanoparticle-based delivery systems can offer a slower and more sustained drug release profile under optimized design conditions. Hence, the plasma concentration-time profile is characterized by lower peak drug concentrations, prolonged maintenance within the therapeutic window, and a more gradual decline in drug concentration. Controlled drug release from nanoparticles has the potential to improve therapeutic efficacy and the overall safety profile by minimizing burst release and peak concentration-associated toxicity while maintaining sustained therapeutic drug exposure.

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  Figure 3. Key mechanisms of pathological cardiac hypertrophy and nanoparticle-based therapeutic strategies (created with BioRender.com). Pathological cardiac hypertrophy is regulated by multiple mechanisms, including transcription and epigenetic regulation, signal transduction, metabolic remodeling, inflammation, and extracellular matrix (ECM) remodeling. Additionally, nanoparticle-based therapies mainly include gene and epigenetic nanotherapy, anti-oxidative nanotherapy, anti-inflammatory nanotherapy, and anti-fibrotic nanotherapy. Horizontal arrows indicate cellular transitions. Upward and downward arrows indicate increased and decreased levels of the corresponding molecules, respectively. Cross symbols denote inhibition of pathological processes. Bidirectional arrows indicate crosstalk and reciprocal interactions among these pathological mechanisms.

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  Figure 4. Cardiac delivery barriers and design principles of nanoparticles for cardiac hypertrophy (created with BioRender.com). (A) Major biological barriers limiting cardiac delivery, including impaired vascular extravasation, protein Corona formation, and systemic clearance. (B) Major nanomaterial platforms, including inorganic nanoparticles, organic nanoparticles, and biomimetic nanoparticles. (C) Targeting strategies of nanoparticles, including passive targeting, active targeting achieved through ligand-receptor interactions, and biomimetic targeting based on the properties of natural membranes. (D) stimuli-responsive release strategies. (E) Administration routes, including intravenous injection, intraperitoneal injection, intradermal injection, inhalation, and oral administration.