Targeted co-delivery of bee venom and chemotherapeutics via natural sporopollenin microcapsules potently suppresses breast and colorectal cancer cells

The development of intracorporeal microcarriers capable of targeted and synergistic co-delivery remains a significant challenge in drug delivery. This study addresses underexplored approaches by combining bee venom (BV) as a chemotherapeutic potentiator with sporopollenin microcapsules (SMCs), using molecular modeling to elucidate drug–carrier interactions governing loading/release, along with determining if BV enables reduced drug doses while enhancing efficacy. SMCs were prepared from bee pollen and loaded via a vacuum-assisted protocol with tamoxifen (TAM), 5-Fluorouracil (5-FU), BV, or TAM/5-FU +BV combinations. Loaded-SMCs were coated with 15% Eudragit (Eud) for pH-triggered intestinal/colonic release. In vitro release was profiled in sequential gastrointestinal and colonic fluids. Formulations was tested on breast and colorectal cancer cells and healthy fibroblasts. Quantum chemical calculations were performed to investigate drug–sporopollenin interactions. SMCs achieved high loading: TAM 45%, 5-FU 34%, BV 42%. Eud (15%) markedly reduced premature gastric release (5-FU gastric leakage reduced from 77% to 29%) and shifted release to intestinal/colonic phases. Co-delivery formulations produced strong synergy: co-encapsulated BV allowed achievement of cancer cell kill comparable to full chemotherapeutic doses using roughly half drug concentration (TAM IC 50 2.62 μM; 5-FU IC 50 7.62 μM; BV IC 50 ≈1.3–1.5 μg/mL). Empty SMCs showed excellent biocompatibility with healthy cells. Molecular docking showed stronger TAM–M–SMC binding (E ads ≈ –0.076 eV) than 5-FU (E ads ≈ –0.029 eV), explaining TAM’s slower release. SMCs with Eud coating provide a promising, sustainable platform for intestine/colon-targeted. Co-delivery with BV potentiates chemotherapy, enabling dose reduction and potentially lowering systemic toxicity.