Delivery of TAPI‐1 via Neutrophil Membrane Fusogenic Liposomal Nanoparticles Can Effectively Ameliorate Cardiac Dysfunction in Heart Failure

Nanomedicine has been widely employed as a site-specific and target-oriented drug delivery tactic in treating heart failure (HF). Ischemia-induced inflammation plays a robust role in the development of HF and neutrophil is one of the main immune cell types that rapidly infiltrate into the inflamed tissues after myocardial infarction (MI). In the present study, we examined the efficacy of a formation of biomimetic nanoparticles that were prepared by fabricated TAPI-1 loaded liposomes coated with neutrophil membranes in the treatment of HF. Male SD rats underwent coronary artery ligation (CL) to induce HF. These HF rats were treated with intravenous injection of TAPI-1-loaded biomimetic nanoparticles (n=6) or TAPI-1 alone (n=6) for 4 weeks. The left ventricular (LV) function was assessed by echocardiography within 24 hours and 4 weeks after CL. The nanoparticles were evaluated prior to the treatments. Compared with non-coated formation, neutrophil membrane-coated nanoparticles have high uptake into LPS-stimulated cardiac cells or endothelial cells. Moreover, the coated nanoparticles exhibited higher cell-specific targeting potential and internalization capacity than non-coated nanoparticles in LPS-stimulated endothelial cells. Small animal imaging showed that DiR-labeled nanoparticles were mainly accumulated in the injured heart after MI. Compared with HF rats treated with TAPI-1 alone, the HF rats treated with TAPI-1-loaded nanoparticles had significantly (* p<0.05) improved anatomic indicators with reduced ratio (%) of heart/body weight (0.34 ± 0.042* vs. 0.48± 0.11) and lung/body weight (0.84 ± 0.19* vs. 1.14 ± 0.15). Additionally, one 4-week treatment with TAPI-1-loaded biomimetic nanoparticles reduced LV end systolic volume (0.67±0.032* vs. 0.83±0.036, mL) when compared with the TAPI-1 alone. While LV stroke volume (LVSV) did not change significantly in IV TAPI-1-treated HF animals, LVSV (0.47±0.043* vs. 0.27±0.029, mL) was significantly increased in HF rats treated with TAPI-1-loaded nanoparticles at 4 weeks vs. 24 hours after CL. LV end diastolic volume, LV ejection fraction, and LV infarction zone didn't exhibit significant differences between two treatment groups. Cardiac hemodynamic measurements revealed that the HF rats treated with TAPI-1-loaded nanoparticles had decreased LV end diastolic pressure (10.53±1.67* vs. 19.01±3.32, mmHg) and elevated dP/dtmax (8202.65±658.09* vs. 5994.47±630.81) compared with the HF rats-treated with TAPI-1 alone. Histological evaluation indicated that the fibrosis areas surrounding the infarction scar were significant reduced (15.97±1.84* vs. 22.86±2.27, %) in HF rats treated with TAPI-1-loaded nanoparticles vs. TAPI alone. Flow cytometric analysis also demonstrated that treatment with TAPI-1-loaded nanoparticles improved inflammatory conditions indicated by increased ratio of CD4+ /CD8+ T Cells (2.40±0.67* vs. 1.56±0.21) in the blood and reduced percentage of leukocytes in the heart of HF. These data indicate that neutrophil membrane fusogenic liposomal nanoparticle is an effective drug delivery approach in treating this devastating disease. (Supported by NIH grants R01 HL-139521 & HL-155091 to SGW, S10 OD019941 to RW).