Gel-to-Coacervate Transition in Peptide/HA Complexes for MMP-9-Activated Penetration into Tumor Spheroids

Short phase-separating peptides serve as liquid-based vehicles due to their remarkable fluidity and cell permeability, holding great promise in diffusion-limited applications such as intracellular drug delivery or penetration into deep-seated tumors. However, tuning the phase stability and the phase-transition sensitivity of these coacervates in response to specific pathological signals remains a significant challenge. To tackle this challenge, this study presents a phase-separating peptide/hyaluronic acid (HA) complex coacervate system, which undergoes a solid-to-coacervate transition upon exposure to matrix metalloproteinase 9 (MMP-9). By harnessing this disease-relevant enzyme, overexpressed in the ovarian tumor microenvironment, we further demonstrate the improved infiltration of the coacervates into Hey cells and tumor spheroids. These observations highlight the feasibility of modulating phase behaviors and advanced functions of coacervates through sequence-specific monomer design, offering a practical strategy for the on-target delivery of coacervates and medicine into tumors.