Hyperactivity of signal transducer and activity of transcription 3 (STAT3) plays a crucial role in melanoma invasion and metastasis. Gene therapy applying siRNA targeting STAT3 is a potential therapeutic strategy for melanoma. In this article, we first fabricated safe and novel dissolving microneedles (MNs) for topical application of STAT3 siRNA to enhance the skin penetration of siRNA and used polyethylenimine (PEI, 25 kDa) as carrier to improve cellular uptake of siRNA. The results showed that MNs can effectively penetrate skin and rapidly dissolve in the skin. In vitro B16F10 cell experiments presented that STAT3 siRNA PEI complex can enhance cellular uptake and transfection of siRNA, correspondingly enhance gene silencing efficiency and inhibit tumor cells growth. In vivo experiments indicated that topical application of STAT3 siRNA PEI complex delivered by dissolving MNs into skin can effectively suppress the development of melanoma through silencing STAT3 gene, and the inhibition effect is dose-dependent. STAT3 siRNA delivery via dissolving MNs is a promising approach for skin melanoma treatment with targeting inhibition efficacy and minimal adverse effects.Melanoma, a severe malignant tumor, initiates in melanocytes 1 . It leads to ~75% deaths associated with skin cancer 2 . In recent years, the incidence of melanoma is dramatically increasing 3 . Melanoma is hard to cure and causes high mortality in the clinic due to poor prognosis, aggressive local growth, high rate of metastasis, and resistance to traditional radiotherapy 4 . The typical therapeutic options for melanoma include surgical resection, chemotherapy, immunotherapy, radiotherapy, and biotherapy 5 . However, the therapeutic efficacy of these approaches is restricted due to drug resistance, high toxicity, and poor selectivity 1,6-8 . Small interfering RNA (siRNA) therapy is a promising gene therapy for tumor with relative low toxicity and high specificity 1,[6][7][8][9] . In most malignant tumors, signal transducer and activator of transcription 3 (STAT3) is related to malignant behaviors including tumor proliferation, metastasis, angiogenesis, survival, and immune evasion 10 , and it is hyperactive in many malignant cancers such as breast cancer, prostate cancer, and melanoma [11][12][13] . The activation of STAT3 can increase the code of apoptosis inhibition genes Bcl-xl, Bcl-2, Mcl-1, and survivin 14 , and improve the expression of cell cycle regulatory cyclin D1 and myc 15,16 . The tumor cell apoptosis is consequently inhibited. Moreover, activated STAT3 in melanoma can directly combine to matrix metalloproteinase-2 (MMP-2) gene promoter to increase the expression of MMP-2. MMP-2 degrades extracellular matrix, thus promoting the invasion and metastasis of tumor cells [15][16][17] . Finally, the activated STAT3 improves the expression of VEGF in melanoma to stimulate angiogenesis of tumor and enhance the tumor vascular permeability [17][18][19][20] . Overall, sustained abnormal activation of STAT3 can inhibit tumor cell apoptosis, promote tu...

The hybrid system based on nanoparticles (NPs) self-assembled by the conjugations of hyaluronic acid with cholesterol (HA–Chol NPs) combined with nicotinamide (NIC) for tacrolimus (FK506), ie, FK506 NPs–NIC, has been confirmed to exhibit a significant synergistic effect on FK506 permeation through and into intact skin; thus, it may be a promising approach for FK506 to effectively treat skin diseases. The aim of this study was to evaluate its potential for the treatment of psoriasis. In vitro permeation through the psoriatic skin was carried out, and the results revealed that the combination of NPs with NIC exhibited a significant synergistic effect on FK506 deposition within the psoriatic skin (3.40±0.67 μg/cm 2 ) and penetration through the psoriatic skin (30.86±9.66 μg/cm 2 ). The antipsoriatic activity of FK506 NPs–NIC was evaluated through the treatment for imiquimod (IMQ)-induced psoriasis. The psoriasis area and severity index (PASI) score demonstrated that FK506 HA–Chol NPs–NIC exerted the effect on ameliorating the skin lesions comparable to clobetasol propionate (a positive drug for psoriasis) and superior to commercial FK506 ointment (Protopic ® ), and the histological study showed that it presented a synergistic effect on antipsoriasis after FK506 incorporation into NPs combined with NIC hydrotropic system, which might ultimately increase the therapeutic effect and minimize the systemic side effects by reducing the overall dose of FK506. RAW 264.7 cell uptake presented the enhancement of drugs delivered into cells by HA–Chol NPs–NIC. The antiproliferative activity on HaCaT cells identified that FK506 HA–Chol NPs–NIC exhibited significant inhibiting effects on HaCaT proliferation. The results support that the combination of HA–Chol NPs with NIC is a promising approach for FK506 for the treatment of psoriasis.

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Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506–NPs–NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506–NPs–NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA–Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 μg/cm 2 ) and penetration through the skin (13.38±2.26 μg/cm 2 ). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs–NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA–Chol–NPs–NIC can synergistically improve the percutaneous delivery of FK506, and it is a novel potential strategy based on a nano-sized carrier for FK506 to treat skin diseases.