Shi Yang

Nucleus-Localizing Coacervates Synergize with Chemotherapy for the Treatment of Drug-Resistant Ovarian Tumors

Tumor-targeting intracellular chemotherapy represents a precision therapy to overcome multidrug resistance (MDR) in ovarian cancers, yet efficient drug enrichment in resistant cells is difficult. Peptide-based coacervates have emerged as an intracellular reservoir for drug delivery; however, enhancing their antitumor efficacy requires precise control over the spatiotemporal distribution of drugs within tumor cells. To address this, we developed a nucleus-localizing coacervate system by complexing a cell-penetrating peptide with sodium alginate (SA), which enables efficient delivery of the DNA-binding drug doxorubicin (DOX) into the cell nucleus. Remarkably, the fluorescence partition coefficient of DOX in the nucleus of ovarian cancer cells increased by 4 ± 0.5-fold compared to coacervate-free controls, while nuclear drug retention was extended from approximately 4 to 36 h. This nucleus-localized drug delivery and sustained retention enhanced the killing efficacy of DNA-targeting medicine against MDR cells by 60 ± 5% at clinical doses, offering a promising therapeutic strategy for treating drug-resistant ovarian cancers. Keywords: complexed coacervates, intracellular drug delivery, ovarian cancer, multi-drug resistance, cell-penetrating peptide.

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.