Nanoparticles engineered to combat cancer and other life-threatening diseases may significantly improve patient outcomes. However, inefficient nanoparticle delivery to tumors limits their use and necessitates the development of complex delivery approaches. Here, we examine this issue by harnessing the tumor-homing abilities of human mesenchymal stem cells (MSCs) to deliver a decoupled theranostic complex of rare earth-doped nanoparticles (dNPs) and photosensitizer chlorin e6 (Ce6) to tumors. We show that both bone-marrow- and skin-derived MSCs can transport the dNP-Ce6 complex inside tumor spheroids, which is challenging to accomplish by passive delivery alone. MSCs deliver the dNP-Ce6 complex across the tumor spheroid, facilitating more effective photodynamic damage and tumor destruction than passively accumulated dNP-Ce6. The dNP-Ce6 complex also provides the built-in ability to monitor the MSC migration without causing undesired phototoxicity, which is essential for maximal and side-effect-free delivery of nanoparticles. Our results demonstrate how MSCs can be used as delivery vehicles for the transportation of the dNP-Ce6 complex, addressing the limitations of passive nanoparticle delivery and providing light-based theranostics.

Current efforts to improve photodynamic therapy focus on nanomaterials that integrate deep tissue imaging with efficient reactive oxygen species generation. Gold nanoclusters (Au NCs) are promising alternatives to conventional photosensitizers due to their effective ROS production and enhanced biocompatibility when stabilized by a protein corona. However, both photosensitizers and Au NCs are typically activated by ultraviolet or visible light, which cannot penetrate deeper into tissues and is limited to superficial applications. Here, we report a near-infrared (NIR)-activated photodynamic nanoplatform based on core–shell upconverting nanoparticles (UCNPs; NaGdF₄:Yb³⁺,Er³⁺@NaGdF₄:Yb³⁺,Nd³⁺), functionalized with a protein corona containing bovine serum albumin-stabilized Au NCs (BSA–Au NCs) and photosensitizer chlorin e6 (Ce6). Spectroscopic data confirmed the formation of the UCNP-BSA–Au-Ce6 nanoplatform and demonstrated 32% energy transfer efficiency from UCNPs to Ce6, resulting in efficient reactive oxygen species generation under 808 nm irradiation. Cellular experiments confirmed the effective internalization and optimal biocompatibility of the nanoplatform in human breast cancer and healthy cells. Upon irradiation at 808 nm, the nanoplatform significantly reduced the viability of MDA-MB-231 cancer cells. These findings indicate that the UCNP-BSA–Au-Ce6 nanoplatform couples NIR activation with enhanced singlet oxygen production, providing a multifunctional platform for deep tissue imaging and NIR-activated photodynamic therapy.

Current efforts in improving photodynamic therapy focus on nanomaterials that integrate deep-tissue imaging with efficient reactive oxygen species generation. Gold nanoclusters (Au NCs) are promising alternatives to conventional photosensitizers due to their effective ROS production and enhanced biocompatibility when stabilized by protein corona. However, both photosensitizers and Au NCs are typically activated by ultraviolet or visible light, which cannot penetrate deeper into tissues and is limited to superficial applications. Here, we report a near-infrared (NIR)-activated photodynamic nanoplatform based on core-shell upconverting nanoparticles (UCNPs; NaGdF₄:Yb³⁺,Er³⁺@NaGdF₄:Yb³⁺,Nd³⁺), functionalized with a protein corona containing bovine serum albumin-stabilized Au NCs (BSA-Au NCs) and photosensitizer chlorin e6 (Ce6). Spectroscopic data confirmed the formation of the UCNP-BSA-Au-Ce6 nanoplatform and demonstrated 32% energy transfer efficiency from UCNPs to Ce6, resulting in efficient reactive oxygen species generation under 808 nm irradiation. Cellular experiments confirmed effective internalization and optimal biocompatibility of the nanoplatform in human breast cancer and healthy cells. Upon 808 nm irradiation, the nanoplatform significantly reduced viability of MDA-MB-231 cancer cells. These findings indicate that the UCNP-BSA-Au-Ce6 nanoplatform couples NIR activation with enhanced singlet oxygen production, providing a multifunctional platform for deep-tissue imaging and NIR-activated photodynamic therapy.