Fabrication and evaluation of quinine-loaded chitosan-polycaprolactone core-shell polymeric nanoparticles for the treatment of malaria: an in vitro and in silico study

Malaria remains a major global health challenge, worsened by the rise of drug-resistant <i>Plasmodium falciparum</i>. Quinine is a cornerstone therapy for severe malaria, yet its clinical use is limited by rapid clearance, dose-dependent toxicity, and a narrow therapeutic window. To address these challenges, we developed chitosan-functionalized poly(ε-caprolactone) core-shell nanoparticles (QN-PCL/CS NPs) for enhanced quinine delivery. Fabricated <i>via</i> double emulsion solvent evaporation, the nanoparticles exhibited favorable characteristics: 312.9 ± 11.7 nm diameter, +30.8 ± 1.5 mV zeta potential, and 81.8 ± 6.9% encapsulation efficiency. <i>In vitro</i> studies confirmed efficient drug incorporation and sustained biphasic release. Notably, QN-PCL/CS NPs significantly improved the therapeutic safety profile, increasing the cytotoxicity IC₅₀ in Vero cells from 131.93 µg/mL (free quinine) to 345.93 µg/mL, while enhancing antiplasmodial activity against chloroquine-resistant <i>P. falciparum</i> (FCR3 strain), lowering the IC₅₀ from 130.12 ng/mL to 32.56 ng/mL. This dual improvement resulted in an approximately ten-fold increase in the selectivity index (from 1.014 to 10.658) and a two-fold increase in quinine penetration into infected erythrocytes. Complementary <i>in silico</i> analyses revealed molecular mechanisms underlying these effects: density functional theory identified quinine's reactive sites, and molecular docking predicted strong binding to chitosan (-4.02 kcal/mol) and PCL (-3.99 kcal/mol), explaining the high encapsulation efficiency. Together, these results demonstrate that QN-PCL/CS NPs offer a promising platform for drug-resistant malaria treatment, simultaneously addressing efficacy and toxicity challenges. This integrated <i>in silico-in vitro</i> approach provides both a therapeutically enhanced nanoformulation and a mechanism-guided blueprint for rational design of polymer-based drug delivery systems.