pH-responsive alginate-inulin composite hydrogels incorporating pollen exine capsules for oral protein delivery:...

Proteases are readily inactivated in the gastrointestinal tract, which severely limits their oral delivery. In this study, a pH-responsive composite hydrogel system was developed by embedding papain-loaded Nelumbo nucifera sporopollenin exine capsules (PNSECs) within a sodium alginate-inulin-Al³⁺ matrix to form PNSECs-SAI. Optimized loading yielded an enzyme activity retention of 56.12%. Structural characterization, swelling behavior, and release analyses indicated that the composite matrix remained relatively compact under acidic conditions but underwent pronounced swelling and structural loosening under near-neutral conditions. Accordingly, the apparent cumulative active release of papain was strongly restricted at pH 2.0, remaining below 5% within 5 h and reaching only about 25% after 40 h, whereas rapid release occurred at pH 7.4, approaching 94-100% within 3 h. Simulated oral-gastric-intestinal digestion further showed that PNSECs-SAI substantially improved papain protection, with bioaccessible papain activity reaching 43.79%, compared with 10.71% for PNSECs alone and 3.71% for free papain. These findings suggest that the system may operate through a hierarchical dual-protection effect, in which the outer pH-responsive hydrogel regulates macroscopic protection and release, while the inner sporopollenin capsules provide local confinement and additional diffusion resistance. Overall, PNSECs-SAI represents a promising proof-of-concept platform for pollen-derived oral enzyme delivery.