Co-dispersion-mediated stabilization of a poorly soluble palmitoylation inhibitor within an alginate hydrogel for localized ferroptosis therapy.

Stabilizing high-loadings of hydrophobic small molecules in aqueous systems remains challenging due to crystallization and phase separation, which limit their therapeutic application. Here, we report a co-dispersion-mediated interfacial stabilization strategy that enables high-loading delivery of the poorly soluble palmitoylation inhibitor 2-bromopalmitic acid (2-BP) within an injectable alginate hydrogel system. Through high-shear co-dispersion with Fe₃O₄ nanoparticles, 2-BP undergoes amorphization and is stabilized in a uniformly dispersed state via interfacial interactions and spatial confinement within the hydrogel network, effectively suppressing crystallization and supporting stable dispersed loading under high-concentration conditions. The resulting hydrogel exhibits pH-responsive and coordinated release of 2-BP and Fe²⁺ under mildly acidic tumor conditions, supporting sustained local drug exposure. Functionally, the co-delivery system significantly enhances oxidative stress and tumor suppression both in vitro and in vivo. Mechanistically, these effects are associated with disruption of redox homeostasis and downregulation of the SLC7A11-GPX4 antioxidant axis, thereby promoting ferroptosis. Collectively, this work establishes a co-dispersion-based formulation strategy for achieving high-loading and stable delivery of poorly soluble small-molecule drugs, providing a generalizable strategy for stabilizing poorly soluble hydrophobic drugs under high-loading conditions.