Both T-cell deprivation and insufficient tumor immunogenicity seriously hinder the efficacy of immunemediated tumor destruction in melanoma. In this work, an amphiphilic polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane) copolymer with a thermally sensitive flowable core (mPEG-b-PHEP) was chosen to incorporate IR780 dye and manganese zinc sulfide nanoparticles (ZMS) to form polymer micelles (denoted PP IR780-ZMS ), which precisely controlled the release of ZMS after being triggered by nearinfrared light (NIR). Mn 2+ -mediated chemodynamic therapy (CDT) by photothermal trigger boosted the generation of reactive oxygen species (ROS), making the PP IR780-ZMS smart bomblets in vivo. It was demonstrated that PP IR780-ZMS could maximize immunogenic cell death (ICD) in cancer, which is characterized by abundant damage-associated molecular pattern (DAMP) exposure. As a result, the cytotoxic T cells (CD8 + ) and helper T cells (CD4 + ) expanded and infiltrated the neoplastic foci, which further reprogrammed the suppressive tumor microenvironment (TME) against the primary tumor and pulmonary metastases with safe systemic cytokine expression. In addition, Mn 2+ -mediated cGAS-STING signaling pathway activation enhanced the antitumor immunity of this nanocomposite, providing a practical strategy for expanding the use of Mn-based nanostructures.

Background Psoriasis is a chronic relapsing immunological skin disease characterized by multiple cross-talk inflammatory circuits which are relevantly associated with abnormal cross-reactivity between immune cells and keratinocytes (KCs). It may be inadequate to eradicate complicated pathogenesis only via single-mode therapy. To provide optimal combinatory therapeutics, a nanocomposite-based hydrogel was constructed by loading methotrexate (MTX) into ZnO/Ag to realize combined multiple target therapy of psoriasis. Results In this composite hydrogel, ZnO hybrid mesoporous microspheres were utilized both as drug carriers and reactive oxygen species (ROS)-scavenging nanoparticles. A proper amount of Ag nanoparticle-anchored ZnO nanoparticles (ZnO/Ag) was functionalized with inherent immunoregulatory property. The experiments showed that ZnO/Ag nanoparticles could exhibit a self-therapeutic effect that was attributed to reducing innate cytokine profiles by inactivating p65 in proinflammatory macrophages and abrogating secretion of adaptive cytokines in KCs by downregulating ROS-mediated STAT3-cyclin D1 signaling. A preferable antipsoriatic efficacy was achieved via topical administration of this hydrogel on the imiquimod (IMQ)-induced psoriasis mice model, demonstrating the superior transdermal delivery and combined enhancement of therapeutic efficacy caused by intrinsic nanoparticles and extrinsic MTX. Conclusion This composite hydrogel could serve as a multifunctional, nonirritating, noninvasive and effective transcutaneous nanoagent against psoriasis. Graphical Abstract

Reactive oxygen species (ROS) at supraphysiological concentration have a determinate role in contributing to immuno-metabolic disorders in the epithelial immune microenvironment (EIME) of psoriatic lesions. With an exclusive focus on the gene-oxidative stress environment interaction in the EIME, a comprehensive strategy based on ROS-regulating nanomedicines is greatly anticipated to become the mainstay of anti-psoriasis treatment. This potential therapeutic modality could inhibit the acceleration of psoriasis via remodeling the redox equilibrium and reshaping the EIME. Herein, we present a marked overview of the current progress in the pathomechanisms of psoriasis, with particular concerns on the potential pathogenic role of ROS, which significantly dysregulates redox metabolism of keratinocytes (KCs) and skin-resident or -infiltrating cells. Meanwhile, the emergence of versatile nanomaterial-guided evolution for transdermal drug delivery has been attractive for the percutaneous administration of antipsoriatic therapies in recent years. We emphasize the underlying molecular mechanism of ROS-based nanoreactors for improved therapeutic outcomes against psoriasis and summarize up-to-date progress relating to the advantages and limitations of nanotherapeutic application for transdermal administration, as well as update an insight into potential future directions for nanotherapies in ROS-related skin diseases. Graphical Abstract