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.
Radiation therapy (RT) remains the primary treatment modality for advanced cervical cancer, however, recurrence due to radioresistance presents a significant challenge. Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) are key contributors to this resistance, driven by their inherent radioresistance and radiation-induced phenotypic adaptations. Addressing this issue requires strategies specifically designed to target CAFs and enhance their radiosensitivity. In this study, we developed a biomimetic metal–organic framework (MOF) nanoplatform for the dual-targeted co-delivery of the FAK inhibitor IN10018 and Bismuth (Bi), aimed at improving radiosensitivity in cervical cancer. The IN10018 and Bi-loaded zeolitic imidazolate framework 8 (ZIF-8) nanoparticles (IZB) were further coated with hybrid membranes derived from CAFs and cancer cells, enabling precise targeting of both cell types. Upon exposure to an acidic environment, the nanoparticles disassemble, releasing IN10018, which reduces CAFs infiltration and enhances radiosensitivity. Simultaneously, the incorporation of Bi enhances radiation absorption efficiency, further sensitizing tumor cells to radiotherapy. This dual-target strategy represents a promising approach to overcoming radioresistance in cervical cancer and exemplifies how integrating nanotechnology with targeted therapies can enhance RT efficacy and improve patient outcomes. Graphic Schematic Illustration of IZB@CCM Construction and Application for Cervical Cancer to Improve Radiosensitivity. (1) IZB was fabricated through the one-pot method. (2) Preparation of hybrid CAF-cancer cell membrane. (3) IZB@CCM were obtained by co-extrusion of IZB and hybrid membrane (CCM). (4) IZB@CCM demonstrated the ability to target CAFs and cancer cells. (5) IZB@CCM inhibited the expression of FAK and released radiosensitizer Bi to enhance the radiosensitivity of cervical cancer.
Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a consensus in clinical trials to explore how to arouse anti-tumor immunity and meanwhile overcome the poorly tumoricidal effect and the stroma barrier that greatly hinders drug penetration. To address this challenge, a comprehensive strategy is proposed to fully utilize both the ferroptotic vulnerability of PDAC to potently irritate anti-tumor immunity and the desmoplasia-associated focal adhesion kinase (FAK) to wholly improve the immunosuppressive microenvironment via sustained release of drugs in an injectable hydrogel for increasing drug penetration in tumor location and averting systematic toxicity. The injectable hydrogel ED-M@CS/MC is hybridized with micelles loaded with erastin that exclusively induces ferroptosis and a FAK inhibitor defactinib for inhibiting stroma formation, and achieves sustained release of the drugs for up to 12 days. With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and Kras G12D -engineered primary PDAC mice and synergistically promotes the infiltration of CD8 + cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC.
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