Light-Triggered Gold Nanoparticles Remodel Tumor Architecture to Enhance Drug Penetration

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by a dense “physical fortress” of robust intercellular adhesion, which severely limits the accessibility of chemotherapeutics, including nanomedicines. This transport barrier hampers the even accumulation of therapeutic agents throughout the whole of the tumor, where sublethal concentrations drive resistance and recurrence. To address this, we report a strategy using gold nanoparticle (AuNP)-mediated transient photothermal treatment to mechanically modulate the 3D tumor architecture of PANC-1 spheroids. By utilizing AuNPs as localized photothermal transducers, we demonstrate that controlled AuNP-mediated hyperthermia remodels the architecture of PANC-1 spheroids, resulting in reduced structural cohesion. This transient structural relaxation significantly increases accessibility within the 3D spheroid architecture and enhances the depth-resolved accumulation of doxorubicin. Unlike traditional thermal ablation, this priming approach focuses on permeabilizing the tumor ecosystem to enhance delivery. While the standard-of-care FOLFIRINOX chemotherapeutic regimen displays limited efficacy in these dense spheroids, AuNP-assisted irradiation significantly enhances the therapeutic response. The combined FOLFIRINOX + AuNPs + laser treatment produces an enhanced reduction in spheroid viability, outperforming all individual modalities. Our findings highlight AuNP-mediated photothermal priming as a powerful adjunctive tool to transiently modulate the physical barriers of PDAC, potentially improving accessibility to therapeutic molecules.