Volkan Aylanç, Seymanur Ertosun, Nuno Vale, Cristina Freire, Miguel Vilas‐Boas
ABSTRACT Sporopollenin, a highly robust, biocompatible, and chemically resistant biopolymer derived from pollen grains, represents an underexploited renewable resource for sustainable pharmaceutical applications. Therewith, the broader application of oral pollen‐based systems is restricted by morphology‐related limitations, premature gastric release, and insufficient intestinal adhesion. Herein, sporopollenin microcapsules (SMCs) were produced from Castanea sp. (Cas) and Helianthus sp. (Hel) bee pollen using a solvent‐efficient, scalable purification strategy. The microcapsules were then surface‐functionalized via a clean photochemical approach to enhance mucoadhesion and coated with either biodegradable alginate (Alg) or pH‐responsive eudragit (Eud), modulating the controlled intestinal release of the model drug 5‐Fluorouracil (5‐FU). Scanning electron microscope (SEM), confocal laser scanning microscopy (CLSM), and laser diffraction particle analysis confirmed successful purification, with average sizes of 11.2 μm (Cas) and 24.1 μm (Hel). Drug loading capacities were 29% and 36%, respectively, and Fourier‐transform infrared (FTIR) and thermogravimetric analysis (TGA) validated successful encapsulation. Uncoated SMCs released 63%–73% of 5‐FU within 1 h, whereas Alg or Eud coatings delayed release, achieving sustained, super case‐II transport profiles. Bioadhesion testing showed Hel‐SMCs had a higher work of adhesion (0.298 mJ/cm 2 ) than Cas‐SMCs (0.079 mJ/cm 2 ), supporting prolonged residence in the target site. Biocompatibility assays of SMCs in Vero cells indicated no cytotoxic effects, GI 50 > 700 μg/mL. Overall, polymer‐coated SMCs demonstrate strong potential as sustainable oral drug delivery systems, integrating effective encapsulation, controlled and mucoadhesive release behavior with multifunctional, low‐waste design principles that advance sustainable pharmacy and resource efficiency.