Innovative Design of Fluorescent PLGA -1,8-Naphthalimide Nanoparticles as Multifunctional Materials for Next-Generation Nanotechnology and Biomedicine

Abstract

The rational design of polymeric nanomaterials is entering a new stage with the integration of computational modeling and advanced synthetic control. In this study, we develop a molecular design strategy for fluorescent polymer-based nanoparticles by combining density functional theory (DFT), time-dependent DFT (TD-DFT), and experimental validation. Poly(lactic-co-glycolic acid) (PLGA), a benchmark biodegradable polymer for drug delivery, was covalently modified with tailored 1,8-naphthalimide fluorophores to generate next-generation fluorescent conjugates. By systematically varying the substituent at the 4-position of the aromatic ring and the carbon spacer length, we established clear structure-property correlations governing both spectralluminescent behavior and structural stability. Theoretical calculations successfully reproduced experimental emission features, validating the predictive capacity of our design workflow. The resulting PLGA-1,8-naphthalimide conjugates enabled the preparation of highly emissive, biocompatible nanoparticles with excellent colloidal stability. Cellular imaging confirmed strong fluorescence and homogeneous distribution in both murine 4T1 and transfected HeLa cell lines. These findings demonstrate how data-driven molecular engineering can unlock a new class of functional polymeric materials, bridging computational chemistry and biomedical nanotechnology to advance the next generation of smart fluorescent platforms for imaging and therapeutic applications.New conceptsThe rational molecular design of polymeric drug delivery systems is increasingly driven by computational insight, enabling precise control of structure-function relationships in complex materials. Here, we report an integrated experimental-theoretical approach combining time-dependent density functional theory (TD-DFT) and electronic structure diagnostics to engineer new fluorescent conjugates based on poly(lactic-co-glycolic acid) (PLGA) and 1,8-naphthalimide derivatives. The influence of substituent type at the 4-position of the aromatic ring and the spacer length on the photophysical properties and electronic transitions was systematically explored, establishing structure-property guidelines for effective fluorophore integration without compromising polymer stability or therapeutic compatibility. Guided by these insights, novel PLGA-1,8-naphthalimide conjugates were synthesized and formulated into bright, photostable fluorescent nanoparticles. These nanoparticles exhibit high optical performance and excellent biocompatibility, enabling real-time visualization of their cellular distribution in 4T1 and transfected HeLa cell lines. This study provides a molecular design framework for next-generation polymeric materials that bridge computational modeling and bioimaging functionality, advancing the development of multifunctional nanoplatforms for biomedical and nanotechnological applications.