Zwitterionic, Stimuli-Responsive Liposomes for Curcumin Drug Delivery: Enhancing M2 Macrophage Polarization and Reducing Oxidative Stress through Enzyme-Specific and Hyperthermia-Triggered Release

A zwitterionic, stimuli-responsive liposomal system was meticulously designed for the precise and controlled delivery of curcumin, leveraging enzyme-specific and hyperthermic stimuli to enhance therapeutic outcomes. This platform is specifically engineered to release curcumin in response to <i>phospholipase A2</i>, an enzyme that degrades phospholipids, enabling highly targeted and site-specific drug release. Mild hyperthermia (40 °C) further enhances membrane permeability and activates thermosensitive carriers, optimizing drug delivery. Curcumin encapsulation is facilitated through a combination of zwitterionic and electrostatic interactions, significantly improving both loading capacity and encapsulation efficiency. A design of experiments (DoE) approach was employed to systematically optimize lipid-to-cholesterol ratios and formulation conditions. The liposomal system was thoroughly characterized using dynamic light scattering, zeta potential measurements, and transmission electron microscopy, ensuring stability and structural integrity. Notably, this system effectively encapsulates hydrophobic curcumin while maintaining particle size and bioactivity. <i>In vitro</i> studies revealed robust antioxidant and anti-ROS activities, alongside excellent biocompatibility, with no cytotoxicity observed at concentrations up to 2000 μg/mL. Furthermore, the zwitterionic liposomes enhanced M2 macrophage polarization and reduced oxidative stress. This advanced platform offers a promising, biocompatible solution for targeted curcumin delivery.