Engineered Yolk-Shell Nanocarriers for Biphasic Release and Efficient Codelivery of Chemotherapy Drugs in Lung Cancer...

Lung cancer is the leading cause of cancer-related deaths worldwide, with growing evidence suggesting that exposure to fine particulate matter (PM_2.5) contributes to cancer. However, conventional chemotherapeutics have limitations due to nonspecific biodistribution, systemic toxicity, and challenges in codelivering multiple drugs with different physicochemical properties. Here, we engineered yolk-shell nanoparticles (YSNs) to achieve codelivery of doxorubicin (DOX, hydrophilic) and paclitaxel (PTX, hydrophobic). Rhodamine B (RhB, hydrophilic) and methylene blue (MB, hydrophobic) were also used as model drugs because they have drug release kinetics similar to those of DOX and PTX, respectively. We observed rapid and sustained release of RhB over 14 days and burst release of MB within 24 h. MB or PTX was released from the mesoporous organosilica shell, whereas biphasic RhB or DOX was released from the organosilica surface and silica inner core. Confocal microscopy confirmed the efficient cellular uptake and accumulation of YSNs around the nucleus. Blank YSNs were nontoxic to normal human bronchial epithelial cells (BEAS-2B) and lung cancer cells (A549). In A549 cells, YSNs coloaded with DOX/PTX enhanced in vitro efficacy compared with free drugs, producing equivalent or greater cytotoxicity at reduced drug loadings, approximately 15-fold (DOX) and 10-fold (PTX) lower than the effective doses. These results highlight the potential of the YSN platform for dose-efficient combination chemotherapy and its promising biocompatibility in a drug delivery system.