Architecture-Dependent Stability, Cellular Uptake, and Redox Modulation of Poly(p-Coumaric Acid) Hybrid Nanoparticles for Ovarian Carcinoma Intervention

ABSTRACT The clinical efficacy of fluorescence-guided surgery (FGS) is often compromised by the poor photostability and biologically inert nature of conventional contrast agents such as Indocyanine Green (ICG). While nanocarriers can enhance dye stability, they often function primarily as passive delivery vehicles, requiring additive complexity to achieve therapeutic effects. Here, we report a structure-guided approach to develop self-theranostic hybrid nanoparticles where the polycondensation kinetics of the polymer core, poly(p-coumaric acid) (PCA), serve as a critical design parameter governing nanoparticle assembly and downstream optical and biological performance. By systematically varying the reaction duration, we synthesized PCA variants with distinct polymer growth profiles that influence nanoparticle morphology, ICG encapsulation, and fluorescence stability. The optimized PCA1.5h formulation significantly improved the stability of encapsulated ICG, maintaining robust NIR-I fluorescence under storage and surgical illumination conditions. Beyond acting as a structural scaffold, the PCA matrix retained intrinsic redox-modulating activity, leading to increased reactive oxygen species (ROS) signal generation and reduced viability in multiple ovarian cancer cells. The imaging performance of these nanoparticles was further evaluated using 3D bioprinted intraperitoneal tumor phantoms designed to simulate key optical and spatial features relevant to fluorescence-guided imaging. This work establishes reaction-time-dependent PCA growth profiles as an important formulation parameter for integrating imaging performance and intrinsic biological activity within a simplified hybrid nanomaterial platform. TOC