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.