Chain Length-Regulated Poly(styrene-co-maleic acid)/Lipid Nanostructures for Curcumin Encapsulation

Sustainable strategies for delivering poorly water-soluble drugs remain limited by the need of organic solvents, cosurfactants, or high-energy processing. Here, we report a chain length-regulated poly(styrene-co-maleic acid) (PSMA)/lipid nanocarrier platform for hydrophobic drug encapsulation in aqueous media. A series of low molecular weight PSMAs was synthesized via carbon tetrabromide (CBr₄)-mediated radical polymerization and combined with saturated phosphatidylcholine lipids with different phase-transition behaviors. Using curcumin as a model compound, we demonstrate that PSMA chain length and styrene/maleic acid composition jointly influence polymer–lipid nanoassembly formation, colloidal stability, and drug loading performance. Low molecular weight PSMA (M_n < 5000 g/mol), when combined with low transition-temperature phosphatidylcholine lipids, promoted lipid reorganization and formation of small polymer–lipid nanoassemblies with apparent diameters of ∼10–13 nm and improved storage stability. In contrast, higher molecular weight PSMA produced larger, less uniform aggregates but increased curcumin encapsulation efficiency, likely due to stronger hydrophobic drug-polymer interactions. Curcumin incorporation increased the apparent particle size to ∼80–200 nm, reflecting drug-associated structural reorganization. Most curcumin-loaded PSMA/DLPC formulations showed low cytotoxicity toward normal colon epithelial cells, while maintaining stronger growth-inhibitory activity against colorectal cancer cells. Overall, this work highlights PSMA molecular design as an important factor in tuning polymer–lipid nanoassembly, colloidal stability, and curcumin encapsulation, providing a simple aqueous approach toward lipid-based nanocarriers for hydrophobic drug delivery.