A dual-peptides and specific promoter-modified nano gene delivery system for myocardial hypertrophy treatment

Abstract

Cardiac hypertrophy represents the heart's adaptive response to physiological or pathological stimuli, functioning to alleviate ventricular wall stress and preserve cardiac function and efficiency. However, pathological hypertrophy usually progresses to heart failure. Gene therapy, in contrast to conventional chemotherapeutic drugs, has the ability to impact cardiac hypertrophy directly, while the lack of adequate vectors limits its application. Gemini surfactants (GS) have been proven to be effective for transfection in vivo in earlier research. To diminish the natural liver targeting of GS nanoparticles, a dual-targeted myocardial biomimetic GS nanocomplex gene delivery system with functional peptides TAT and PCM modified and synergized with cardiac-specific promoter chicken cardiac troponin T promoter (cTnT) is designed in this study. Bioluminescence imaging reveals the utility of targeting hypertrophy myocardium, resulting in low localization in the liver upon systemic administration. Biochemical indicators, echocardiography, gross morphology and histology all indicate that GS-nanocomplexes attenuate ISO-induced cardiac hypertrophy. RNA sequencing results reflect different uptake pathways for different GS nanocomplexes, and the investigation of cellular uptake under various endocytosis inhibitors demonstrate that clathrin-mediated endocytosis (CME) serves as the primary endocytic pathway for GS-pDNA uptake and caveolin-mediated endocytosis (CVME) serves as the primary endocytic pathway for GS-pDNA-TP-RBCM uptake. The endocytic pathway for nanocomplexes is confirmed by CAV-1 silencing. In summary, this research presents a dual myocardium-targeted biomimetic GS nanocomplex for gene delivery for cardiomyocytes. The in vivo and in vitro targeting ability, good biocompatibility and helpful therapeutic efficacy for cardiac hypertrophy are verified, and the uptake mechanism and intracellular transport pathway of GS nanocomplex are revealed. This innovative approach provides a promising therapeutic strategy for the treatment of cardiac hypertrophy.