Tumor Microenvironment Responsive Hollow Nanoplatform for Triple Amplification of Oxidative Stress to Enhance Cuproptosis-Based Synergistic Cancer Therapy.

Cuproptosis is a recently discovered form of programmed cell death and shows great potential in cancer treatment. Herein, a copper-dithiocarbamate chelate-doped and artemisinin-loaded hollow nanoplatform (HNP) is developed via a chelation competition-induced hollowing strategy for cuproptosis-based combination therapy. The HNP exhibits tumor microenvironment-triggered catalytic activity, wherein liberated Cu2+ catalyzes artemisinin and endogenous H2 O2 to produce C-centered radicals and hydroxyl radicals, respectively. Meanwhile, the disulfide bonds-rich HNP can deplete intracellular glutathione, thus triply amplifying tumor oxidative stress. The augmented oxidative stress sensitizes cancer cells to the cuproptosis, causing prominent dihydrolipoamide S-acetyltransferase oligomerization and mitochondrial dysfunction. Moreover, the HNP can activate ferroptosis via inhibiting GPX4 activity and trigger apoptosis via dithiocarbamate-copper chelate-mediated ubiquitinated proteins accumulation, resulting in potent antitumor efficacy. Such a cuproptosis/ferroptosis/apoptosis synergetic strategy opens a new avenue for cancer therapy.

Copper-Hydrazide Coordinated Multifunctional Hyaluronan Hydrogels for Infected Wound Healing.

Bacterial infection and delayed healing are two major obstacles in cutaneous wound management, and developing multifunctional hydrogels with antibacterial and prohealing capabilities presents a promising strategy to dress wounds. However, the simple and facile fabrication of such hydrogel dressings remains challenging. Herein, we report the first observation on hydrazide-metal coordination crosslinking that is utilized to successfully construct a series of hyaluronan (HA)-metal hydrogels by mixing hydrazided HA and metal ion solutions. Considering the antibacterial, prohealing, and proangiogenic properties of HA and Cu(II), as a proof of principle, a HA-Cu hydrogel was systematically investigated as a wound dressing. Surprisingly, the hydrazide-Cu(II) coordination was dynamic in nature and imparted the HA-Cu hydrogel with physicochemical multifunctions, including spontaneous self-healing, shear-thinning injectability, reversible pH/redox/ion pair triple responsiveness, etc. Moreover, the HA-Cu hydrogel exhibited a robust broad-spectrum antibacterial activity and could significantly accelerate infectious wound healing. Impressively, glutathione-triggered hydroxyl radical generation further potentiated wound healing, providing a paradigm for on-demand antibacterial activity enhancement. Hence, the HA-Cu hydrogel is a clinically applicable "smart" dressing for multi-scenario wound healing. We envision that the simple and versatile coordination approach opens up a new avenue to develop multifunctional hydrogels and shows great potential in frontier fields, such as biomedicine, wearable devices, and soft robots.