Oral Poly(N-oxide) zwitterionic nanoplatform for Gambogenic Acid Enhances Mucosal penetration for potentiated anti-angiogenic therapy

Oral anti-angiogenic therapy for hepatocellular carcinoma is fundamentally constrained by poor mucus penetration and enterocyte uptake, which limits intestinal absorption and systemic exposure. Moreover, anti-angiogenic therapy inherently reduces tumor vascular density, further restricting intratumoral drug accumulation and creating a therapeutic delivery paradox. Here, we report an oral poly(N-oxide) zwitterionic nanoplatform for gambogenic acid (GNA), termed POC-GNA, that could mechanistically overcome these sequential delivery barriers. POC-GNA nanoparticles confer strong non-fouling properties and a near-neutral surface to facilitate efficient mucus penetration and enterocyte uptake for improved intestinal absorption, while modulating tumor vasculature by reducing the density and increasing the permeability, ultimately enhancing their intratumoral accumulation. Consequently, oral POC-GNA exhibited markedly enhanced intestinal absorption, prolonged systemic circulation, and preferential accumulation in hepatic tumors. The improved bioavailability translated into potent antitumor efficacy through synergistic anti-angiogenic, vascular-disruptive, pro-apoptotic, and immunoregulatory effects. In both subcutaneous and orthotopic HCC models, oral POC-GNA achieved remarkable tumor inhibition rates, surpassing PEGylated formulations administered orally or intravenously. Importantly, oral delivery effectively eliminates the vascular irritation associated with intravenous GNA administration. Collectively, this study addresses a vascular density–dependent drug accumulation bottleneck and establishes a clinically translatable oral nanomedicine strategy for potentiated anti-angiogenic therapy.