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Atopic dermatitis (AD) is a chronic skin disease caused by skin immune dyshomeostasis and accompanied by severe pruritus. Although oxidative stress and mechanical scratching can aggravate AD inflammation, treatment targeting scratching is often overlooked, and the efficiency of mechano-chemically synergistic therapy remains unclear. Here, we find that enhanced phosphorylation of focal adhesion kinase (FAK) is associated with scratch-exacerbated AD. We then develop a multifunctional hydrogel dressing that integrates oxidative stress modulation with FAK inhibition to synergistically treat AD. We show that the adhesive, self-healing and antimicrobial hydrogel is suitable for the unique scratching and bacterial environment of AD skin. We demonstrate that it can scavenge intracellular reactive oxygen species and reduce mechanically induced intercellular junction deficiency and inflammation. Furthermore, in mouse AD models with controlled scratching, we find that the hydrogel alleviates AD symptoms, rebuilds the skin barrier, and inhibits inflammation. These results suggest that the hydrogel integrating reactive oxygen species scavenging and FAK inhibition could serve as a promising skin dressing for synergistic AD treatment.

Proteolysis Targeting Chimeras (PROTACs) represent a promising therapeutic modality to address undruggable and resistant issues in drug discovery. However, potential on‐target toxicity remains clinically challenging. We developed a generalized caging strategy to synthesize a series of stimuli‐responsive PROTACs (sr‐PROTACs) with diverse molecular blocks bearing robust and cleavable linkers, presenting “turn on” features in manipulating protein degradation. By leveraging pathological cues, such as elevated ROS, phosphatase, H2S, or hypoxia, and external triggers, such as ultraviolet light, X‐Ray, or bioorthogonal reagents, we achieved site‐specific activation and traceless release of original PROTACs through de‐caging and subsequent self‐immolative cleavage, realizing selective uptake and controlled protein degradation in vitro. Especially, in vivo study revealed that two sr‐PROTACs with phosphate‐ and fluorine‐containing cages exhibited high solubility and long plasma exposure, and were specifically activated by tumor overexpressing phosphatase or low dosage of X‐Ray irradiation in situ, leading to efficient protein degradation and potent tumor remission. With more reactive biomarkers to be screened from clinical practice, our caging library could provide a general tool to design activatable PROTACs, prodrugs, antibody drug conjugates, and smart biomaterials for personalized treatment, tissue engineering or regenerative medicine.

Thermal therapy has been widely used in clinical tumor treatment and more recently in combination with chemotherapy, where the key challenge is the treatment resistance. The mechanism at the cellular level underlying the resistance to thermo-chemical combination therapy remains elusive. In this study, we constructed 3D culture models for glioma cells (i.e., 3D glioma spheres) as the model system to recapitulate the native tumor microenvironment and systematically investigated the thermal response of 3D glioma spheres at different hyperthermic temperatures. We found that 3D glioma spheres show high viability under hyperthermia, especially under high hyperthermic temperatures (42 °C). Further study revealed that the main mechanism lies in the high energy level of cells in 3D glioma spheres under hyperthermia, which enables the cells to respond promptly to thermal stimulation and maintain cellular viability by upregulating the chaperon protein Hsp70 and the anti-apoptotic pathway AKT. Besides, we also demonstrated that 3D glioma spheres show strong drug resistance to the thermochemical combination therapy. This study provides a new perspective on understanding the thermal response of combination therapy for tumor treatment.