Hyaluronate-Black Phosphorus-Upconversion Nanoparticles Complex for Non-Invasive Theranosis of Skin Cancer

Black phosphorus (BP) has been widely investigated for various biomedical applications with the unique characteristics of 2D nanomaterials including its high photothermal conversion efficiency, biocompatibility, biodegradability and ultraviolet (UV)-meditated reactive oxygen species (ROS) generation. However, the finite depth of light penetration has limited further development of BP-based photomedicines. Here, we developed hyaluronate-BP-upconversion nanoparticle (HA-BP-UCNP) complex for near-infrared (NIR) light mediated multimodal theranosis of skin cancer with photoacoustic (PA) bioimaging, photodynamic therapy (PDT), and photothermal therapy (PTT). In contrast to the conventional BP-based skin cancer theranosis systems, HA-BP-UCNP complex could be non-invasively delivered into the tumor site to induce the cancer cell apoptosis upon NIR light irradiation. HA in the complex facilitated the transdermal delivery of BP into the tumor tissue under the skin. Upon 980 nm NIR light irradiation, UCNP converted the light to UV-blue light to generate ROS by sensitizing BP in the HA-BP-UCNP complex for PDT. Remarkably, 808 nm NIR triggered PTT for the apoptosis of tumor cells. The photoacoustic imaging of BP successfully visualized the non-invasive transdermal delivery of HA-BP-UCNP complex into the mice skin. The cell viability test revealed the low cytotoxicity of HA-BP-UCNP complex in fibroblast cells. On the other hand, the complex showed high cytotoxicity to tumor cells under NIR light irradiation by PDT and PTT. The combination therapy of PDT and PTT by 980 + 808 nm NIR light irradiation drastically reduced tumor growth compared to only single NIR light irradiation for up to 7 days in skin cancer model mice. The antitumor effect of HA-BP-UCNP complex with NIR light irradiation was also confirmed by immunohistochemical TUNEL assay. Taken together, we could demonstrate the feasibility of HA-BP-UCNP complex as a non-invasive theranostic nanoplatform for skin cancer.