Cold-Responsive Hyaluronated Upconversion Nanoplatform for Transdermal Cryo-Photodynamic Cancer Therapy

Cryotherapy leverages controlled freezing temperature interventions to engender a cascade of tumor-suppressing effects. However, its bottleneck lies in the standalone ineffectiveness. A promising strategy is using nanoparticle therapeutics to augment the efficacy of cryotherapy. Here, a cold-responsive nanoplatform composed of upconversion nanoparticles coated with silica - chlorin e6 - hyaluronic acid (UCNPs@SiO2-Ce6-HA) is designed. This nanoplatform is employed to integrate cryotherapy with photodynamic therapy (PDT) in order to improve skin cancer treatment efficacy in a synergistic manner. The cryotherapy appeared to enhance the upconversion brightness by suppressing the thermal quenching. The low-temperature treatment afforded a 2.45-fold enhancement in the luminescence of UCNPs and a 3.15-fold increase in the photodynamic efficacy of UCNPs@SiO2-Ce6-HA nanoplatforms. Ex vivo tests with porcine skins and the subsequent validation in mouse tumor tissues revealed the effective HA-mediated transdermal delivery of designed nanoplatforms to deep tumor tissues. After transdermal delivery, in vivo photodynamic therapy using the UCNPs@SiO2-Ce6-HA nanoplatforms resulted in the optimized efficacy of 79% in combination with cryotherapy. These findings underscore the Cryo-PDT as a truly promising integrated treatment paradigm and warrant further exploring the synergistic interplay between cryotherapy and PDT with bright upconversion to unlock their full potential in cancer therapy. Transdermal cryo-photodynamic therapy (Cryo-PDT) of cancer is demonstrated by using a cold-responsive nanoplatform of hyaluronic acid, chlorin e6, and silica-coated upconversion nanoparticles (UCNPs@SiO2-Ce6-HA). A cryo-driven boost of upconversion brightness in the nanoplatform results in three-times higher singlet oxygen generation and remarkable cancer suppression in melanoma-bearing mice, confirming the feasibility of Cryo-PDT as a promising therapeutic strategy. image