Boosting Oral Chemotherapy Efficacy and Ameliorating Intestinal Dysbiosis via a Microfluidic-Engineered RGD-Targeted Nanoplatform against Breast Cancer

Doxorubicin (DOX) faces significant challenges in oral chemotherapy due to low intestinal permeability and extensive first-pass metabolism. We developed microfluidics-prepared RGD-modified solid lipid nanoparticles (MF-SLNs) to enhance oral anticancer efficacy and investigate their impact on gut microbiota. In vitro analysis showed that MF-SLNs exhibited a smaller particle size (∼120 nm) and a more stable zeta potential (∼20 mV). They also showed high encapsulation efficiency (EE, EE > 80%). Particle size distribution from dynamic light scattering (DLS) and transmission electron microscopy (TEM) further confirmed the improved homogeneity of MF-SLNs (PDI of 0.073). DOX was released from MF-SLNs in a slow and sustained manner, indicating its potential for controlled delivery into the gastrointestinal tract. MF-SLNs showed good stability in simulated gastric and intestinal fluids. Confocal microscopy revealed that MF-SLNs significantly enhanced the transcellular transport of DOX across the FAE monolayer and subsequent uptake by MDA-MB-231 breast cancer cells. In vitro apoptosis in MDA-MB-231 breast cancer cells was assessed by using flow cytometry, revealing an increased percentage of apoptotic cells following MF-SLNs treatment. In vivo studies in nude mice demonstrated enhanced tumor inhibition and improved survival rates. Histopathological analysis, organ weight measurements, and echocardiography detection indicated favorable outcomes, complemented by assessments of tissue damage markers. Furthermore, 16S rRNA sequencing revealed a significant increase in beneficial gut bacteria, including <i>Faecalibacterium</i> and <i>Bacillus</i>, following MF-SLNs treatment. Collectively, MF-SLNs enhance antitumor efficacy and promote healthier gut microbiota, suggesting advantages over traditional DOX formulations. Further studies are needed to optimize this delivery system for breast cancer therapies.