Nanotechnology-based encapsulation of neflamapimod: A new therapeutic strategy for lewy body dementia.

Dementia with Lewy bodies (DLB) remains a therapeutic challenge due to the lack of disease-modifying treatments and the limited brain bioavailability of potential drugs. Neflamapimod (NEFLA), a p38α MAPK inhibitor is one of the few drugs showing potential in this condition. However, a Phase IIB clinical evaluation has shown formulation problems and it has been shown that NEFLA is affected by P-glycoprotein efflux. In this study, we developed and comparatively evaluated four nanoparticle platforms-PLGA, dendritic mesoporous silica (dMSNPs), solid lipid nanoparticles (SLNPs), and invasomes (INV)-to optimize NEFLA delivery. Physicochemical characterization revealed highly homogeneous systems (PDI ≤ 0.2), where SLNPs achieved the highest encapsulation efficiency (89%) and dMSNPs showed superior drug loading (65%). PAMPA assays confirmed that BBB penetration was exclusively achieved by INV-NEFLA and the NPLGA-NEFLA gold standard. INV-NEFLA exhibited superior bioactivity compared to the free drug, inducing morphological ramification in SH-SY5Y and U87-MG cell lines. Most importantly, INV-NEFLA ameliorated mitochondrial dysfunction in DLB patient-derived lymphoblasts by upregulating both oxygen consumption rates and glycolytic reserves. Consequently, INV-mediated nanoencapsulation emerges as a potent delivery system for NEFLA, potentially optimizing therapeutic outcomes in DLB through enhanced efficacy and versatile delivery pathway.