Multi-responsive biopolymer-lipid hybrid nanocarriers for controlled doxorubicin delivery

Hybrid nanocarriers are widely used in anticancer drug delivery because they integrate complementary properties of multiple materials. However, many rely on synthetic surfactants for colloidal stability, which may compromise biocompatibility, while exhibiting limited responsiveness to external stimuli. These challenges highlight the need for more stable and multifunctional delivery platforms. Herein, a surfactant-free biopolymer-lipid hybrid nanocarrier was developed using a lauric acid (LA)/olive oil (OO) lipid core and a bovine serum albumin-hyaluronic acid (BSA : HA) biopolymeric shell. The formulation was optimized using a Taguchi design of experiments (DoE) approach to achieve the desired physicochemical characteristics. The optimized nanoparticles exhibited a sub-200 nm size in water, uniform morphology, and colloidal stability comparable to that of conventionally surfactant-stabilized nanoparticles in various media over 8 weeks. Doxorubicin (DOX) was encapsulated in the optimized HNPs, and in vitro release studies under different conditions demonstrated pH-, enzyme-, and short-term temperature-dependent drug release. Compared with conventionally surfactant-stabilized nanoparticles, the developed HNPs exhibited significantly improved cytocompatibility toward mouse fibroblast (L929) cells. Additionally, DOX-loaded HNPs exhibited significant anticancer activity against human breast cancer (MCF-7) cells. Overall, the developed HNP system combines a surfactant-free formulation, enhanced cytocompatibility, and multi-stimuli-responsive drug release, making it a promising platform for controlled cancer drug delivery.