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

Abstract

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