Neutrophil-mediated delivery of curcumin-loaded manganese-doped zeolitic imidazolate framework-8 nanozymes for pulmonary arterial hypertension.

BACKGROUND

Pulmonary arterial hypertension (PAH) is a severe vascular disease characterized by oxidative stress, inflammation, vascular remodeling, and endothelial‑to‑mesenchymal transition (EndoMT), leading to high pulmonary arterial pressure and right heart failure. Current therapies offer only symptomatic relief without reversing disease progression.

AIM: To develop a targeted nanotherapeutic platform using neutrophil (NE)-mediated delivery of curcumin‑loaded manganese-doped zeolitic imidazolate framework-8 (Mn‑doped ZIF‑8) nanozymes for PAH treatment.

METHODS

We constructed Mn‑ZIF‑8‑Cur@NEs (NEMZC) by loading Mn‑ZIF‑8‑Cur into primary neutrophils. The system was characterized by TEM, XRD, XPS, and drug release assays. In vitro and in vivo studies included transwell migration, immunofluorescence, flow cytometry, ELISA, Western blot, transcriptomics, echocardiography, right‑heart catheterization, and histology in a mouse PAH model.

RESULTS

NEMZC showed high drug loading (encapsulation efficiency ~80%) and pH‑responsive release (82% curcumin release at pH < 6.0 within 12 h). It exhibited excellent targeting, with ~91.7% curcumin released within 4 h under inflammatory stimulation. In vitro, NEMZC reduced α‑SMA expression by 75% and increased CD31 expression by 3.3‑fold, indicating strong anti‑EndoMT effects. It also shifted macrophage polarization, decreasing M1 markers (iNOS by 75%) and increasing M2 markers (CD206 by ~3.2‑fold). In PAH mice, NEMZC reduced pulmonary arterial pressure from 57.2 mmHg to 20.7 mmHg, decreased collagen deposition by ~70%, and modulated the PI3K-NF‑κB pathway.

CONCLUSION

NEMZC represents a safe, targeted, and multifunctional cell‑based nanoplatform that effectively alleviates PAH through dual antioxidant/anti‑inflammatory action and EndoMT inhibition, demonstrating strong potential for clinical translation.