Biodegradable Microembolics with Nanografted Polyanions Enable High-Efficiency Drug Loading and Sustained Deep-Tumor Drug Penetration for Locoregional Chemoembolization Treatment

Transarterial chemoembolization (TACE), the mainstay treatment of unresectable primary liver cancer that primarily employs nondegradable drug-loaded embolic agents to achieve synergistic vascular embolization and locoregional chemotherapy effects, suffers from an inferior drug burst behavior lacking long-term drug release controllability that severely limits the TACE efficacy. Here we developed gelatin-based drug-eluting microembolics grafted with nanosized poly(acrylic acid) serving as a biodegradable ion-exchange platform that leverages a counterion condensation effect to achieve high-efficiency electrostatic drug loading with electropositive drugs such as doxorubicin (i.e., drug loading capacity >34 mg/mL, encapsulation efficiency >98%, and loading time <10 min) and an enzymatic surface-erosion degradation pattern (∼2 months) to offer sustained locoregional pharmacokinetics with long-lasting deep-tumor retention capability for TACE treatment. The microembolics demonstrated facile microcatheter deliverability in a healthy porcine liver embolization model, superior tumor-killing capacity in a rabbit VX2 liver cancer embolization model, and stabilized extravascular drug penetration depth (>3 mm for 3 months) in a rabbit ear embolization model. Importantly, the microembolics finally exhibited vessel remodeling-induced permanent embolization with minimal inflammation responses after complete degradation. Such a biodegradable ion-exchange drug carrier provides an effective and versatile strategy for enhancing long-term therapeutic responses of various local chemotherapy treatments. © 2024 American Chemical Society.