Decoding the Influence of Polyvinyl Alcohol on the Functionalization and Cellular Uptake of Poly(lactic- co -glycolic) Acid Nanoparticles

Molecular Pharmaceutics

Abstract

Abstract Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) are widely investigated drug delivery systems, yet efficient surface functionalization remains challenging. Here, we demonstrate that residual polyvinyl alcohol (PVA), commonly used as a stabilizer during nanoparticle preparation, remains strongly associated with the surface of PLGA NPs and influences their surface properties, functionalization efficiency, and cellular uptake. To investigate this effect, we compared a traditional water-in-oil-in-water (w/o/w) double-emulsion solvent evaporation method with an optimized formulation strategy in which PVA was confined to the internal aqueous phase. The optimized formulation reduced the calculated surface PVA density from 60.68 to 0.83 mg/m2 while requiring only a single purification step. Furthermore, epidermal growth factor (EGF)-functionalized nanoparticles prepared using the optimized method exhibited higher ligand association efficiency and up to 35-fold greater cellular uptake in A549 cells after 24 h compared with nanoparticles prepared using the traditional method. Importantly, both formulations maintained comparable physicochemical stability over 15 days and enabled efficient biomolecule association. Collectively, these findings demonstrate that PVA strongly influences nanoparticle surface characteristics, functionalization efficiency, and cellular interactions, highlighting the importance of surface engineering in the design of functionalized PLGA nanoparticle delivery systems.

Authors 11

1. Fatima Hameedat

   University of Fribourg · University of Groningen

   Affiliation as printed

   University of Fribourg , , Chemin des Verdiers 4 , ,

   University of Groningen , , Antonius Deusinglaan 1 , ,

2. Rasika Daware Aachen

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen University , , ,

3. Ilaria Onori

   University of Fribourg

   Affiliation as printed

   University of Fribourg , , Chemin des Verdiers 4 , ,

4. Jozef Adamčík

   University of Fribourg

   Affiliation as printed

   University of Fribourg , , Chemin des Verdiers 4 , ,

5. Amélie Bazzoni

   University of Fribourg

   Affiliation as printed

   University of Fribourg , , Chemin des Verdiers 4 , ,

6. Federica De Lorenzi Aachen

   Radboud University Nijmegen · University Medical Center · Radboud University Medical Center · RWTH Aachen University

   Affiliation as printed

   RWTH Aachen University , , ,

   Radboud University Medical Centre , , GA ,

7. José Augusto Berrocal

   University of Fribourg · Institut Català d'Investigació Química

   Affiliation as printed

   Institute of Chemical Research of Catalonia (ICIQ) , , Av. da Països Catalans 16 , ,

   University of Fribourg , , ,

   University of Fribourg , , Chemin des Verdiers 4 , ,

8. Barbara Rothen‐Rutishauser

   University of Fribourg

   Affiliation as printed

   University of Fribourg , , ,

   University of Fribourg , , Chemin des Verdiers 4 , ,

9. Alke Petri‐Fink

   University of Fribourg

   Affiliation as printed

   University of Fribourg , , ,

   University of Fribourg , , Chemin des Verdiers 4 , ,

10. Twan Lammers Aachen

    RWTH Aachen University

    Affiliation as printed

    RWTH Aachen University , , ,

11. Flávia Sousa

    University of Fribourg · University of Groningen

    Affiliation as printed

    University of Fribourg , , ,

    University of Fribourg , , Chemin des Verdiers 4 , ,

    University of Groningen , , Antonius Deusinglaan 1 , ,