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.

Psoriatic arthritis (PsA) is a complicated psoriasis comorbidity with manifestations of psoriatic skin and arthritic joints, and tailoring specific treatment strategies for simultaneously delivering different drugs to different action sites in PsA remains challenging. We developed a need-based layered dissolving microneedle (MN) system loading immunosuppressant tacrolimus (TAC) and anti-inflammatory diclofenac (DIC) in different layers of MNs, i.e., TD-MN, which aims to specifically deliver TAC and DIC to skin and articular cavity, achieving simultaneous alleviation of psoriatic skin and arthritic joint lesions in PsA. In vitro and in vivo skin permeation demonstrated that the inter-layer retained TAC within the skin of ∼100 μm, while the tip-layer delivered DIC up to ∼300 μm into the articular cavity. TD-MN not only efficiently decreased the psoriasis area and severity index scores and recovered the thickened epidermis of imiquimod-induced psoriasis but also alleviated carrageenan/kaolin-induced arthritis even better than DIC injection through reducing joint swelling, muscle atrophy, and cartilage destruction. Importantly, TD-MN significantly inhibited the serum TNF-α and IL-17A in psoriatic and arthritic rats. The results support that this approach represents a promising alternative to multi-administration of different drugs for comorbidity, providing a convenient and effective strategy for meeting the requirements of PsA treatment.

Background: Topical application of tacrolimus (FK506) was effective in the treatment of atopic dermatitis (AD); however, adverse effects frequently occurred with the increase of FK506 dose during long–term treatment. Objective: The objective of this project was to develop a hybrid skin targeting system encapsulating FK506 based on nicotinamide (NIC) and chitosan nanoparticles (CS–NPs), ie, FK506–NIC–CS–NPs, which took advantages of both of NIC and CS–NPs to obtain the synergetic effects of percutaneous delivery and treatment efficacy enhancement along with dose reduction. Methods: The formulation of FK506–NIC–CS–NPs was optimized and characterized. In vitro and in vivo skin permeation studies were performed. AD–like skin lesions were constructed with BALB/c mice by 1–chloro–2, 4–dinitrobenzene (DNCB)–induced, and FK506–NIC–CS–NPs containing different dose of FK506 were topically administered to treat AD–like skin lesions in comparison with Protopic. Results: NIC was found to significantly increase the FK506 EE to 92.2% by CS–NPs. In comparison with commercial FK506 ointment (Protopic), in vitro and in vivo skin permeation studies demonstrated that NIC–CS–NPs system significantly enhanced FK506 permeation through and into the skin, and deposited more FK506 into the skin. The treatment efficacy on clinical symptoms, histological analysis, and molecular biology of the AD–mice demonstrated that NIC–CS–NPs with ~1/3 dose of FK506 of Protopic was superior to that of Protopic, and NIC–CS–NPs vehicle exhibited the adjuvant therapy and moderate anti–AD effects. Conclusion: The system of NIC–CS–NPs enhances the permeability of FK506, plays an adjuvant role in anti-AD, reduces the dose of FK506 in treating AD, and is therefore a promising nanoscale system of FK506 for the effective treatment of AD.