Doxorubicin hydrochloride is a potent anticancer agent whose clinical application is limited by dose-dependent cardiotoxicity, poor tumor selectivity, and rapid systemic clearance. Lipid–polymer hybrid nanoparticles (LPHNs) combine the structural integrity of polymeric nanoparticles with the biocompatibility of lipid systems, offering a promising platform for controlled and targeted drug delivery. The present study aimed to design, formulate, and optimize lipid–polymer hybrid nanoparticles for controlled delivery of doxorubicin hydrochloride, with improved encapsulation efficiency, sustained drug release, and enhanced physicochemical stability. Doxorubicin-loaded LPHNs were prepared using a modified nanoprecipitation–self-assembly technique. Six formulations (F1–F6) were developed by varying polymer–lipid ratios. The formulations were evaluated for particle size, polydispersity index (PDI), zeta potential, drug content, encapsulation efficiency, morphology, in-vitro drug release, release kinetics, stability studies, and statistical optimization. All formulations exhibited nanoscale particle size (145–298 nm), negative zeta potential, and high encapsulation efficiency (68–92%). Among them, formulation F4 demonstrated optimized characteristics with particle size 162.4 ± 4.3 nm, PDI 0.214 ± 0.02, zeta potential −28.6 ± 1.4 mV, and sustained drug release up to 48 h (92.1 ± 2.1%). Release kinetics followed the Korsmeyer–Peppas model, indicating anomalous transport. Optimized lipid–polymer hybrid nanoparticles significantly improved the controlled delivery profile of doxorubicin hydrochloride and represent a promising nanocarrier system for cancer chemotherapy.

Doxorubicin hydrochloride, Lipid–polymer hybrid nanoparticles, Controlled drug delivery, Nanoprecipitation, Cancer therapy