To overcome the limitations associated with the targeting abilities of nanotherapeutics and drug loading capacity of mesenchymal stem cells (MSCs), the present study relies on the combination of MSCs tumor tropism with the controlled release function of nano-based drug delivery platforms to achieve tumor-specific accumulation of chemotherapeutics with minimal off-target effects. 5-fluorouracil (5-FU)-containing ceria (CeNPs) coated calcium carbonate nanoparticles (CaNPs) were functionalized with folinic acid (FA) to develop drug-containing nanocomposites (Ca.FU.Ce.FA NCs). NCs were then conjugated with graphene oxide (GO) and decorated with silver nanoparticles (Ag°NPs) to form FU.FA@NS, a rationally designed drug delivery system with O2 generation ca-pacity that alleviates tumor hypoxia for improved photodynamic therapy. Engineering of MSCs with FU.FA@NSs provided successful loading and long-term retention of therapeutics on the sur-face membrane with minimal changes to the functional properties of MSCs. Co-culturing of FU.FA@NS.MSCs with CT26 cells upon UVA exposure revealed enhanced apoptosis in tumor cells through ROS-mediated mitochondrial pathway. FU.FA@NSs released from MSCs were effec-tively taken up by CT26 cells via a clathrin-mediated endocytosis pathway and distributed their drug depots in a pH, H2O2, and UVA-stimulated fashion. Therefore, the cell-based biomimetic drug delivery platform formulated in the current study could be considered a promising strategy for tar-geted chemo-photodynamic therapy of colorectal cancer.

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