Skin diseases are the fourth leading cause of nonfatal and chronic skin diseases, acting as a global burden and affecting the world economy. Skin diseases severely impact the patients' quality of life and have influenced their physical and mental state. Treatment of these skin disorders with conventional methods shows a lack of therapeutic efficacy, long treatment duration, recurrence of the condition, and systemic side effects due to improper drug delivery. However, these pitfalls can be overcome with the applications of advanced nanocarrier- and microneedle (MN)-based transdermal drug delivery strategies that provide efficient site-specific drug delivery at the target site. These advanced transdermal drug delivery strategies can be more effective than other drug administration routes by avoiding first-pass metabolism, enhancing the drug concentration in local skin lesions, and reducing systemic toxicity. Compared with traditional transdermal delivery methods, nanocarrier- or MN-based drug delivery systems are painless, noninvasive, or minimum-invasive and require no expensive equipment. More importantly, they can introduce more advanced functions, including increased skin penetration efficiency, controlled drug release rates, enhanced targeting abilities, and theranostic functions. Here, the emergence of versatile advanced transdermal drug delivery systems for the transdermal delivery of various drugs is reviewed, focusing on the design principles, advantages, and considerations of nanocarrier- and MN-based transdermal drug delivery strategies and their applications in treating diverse skin diseases, including psoriasis, dermatitis, melanoma, and other skin diseases. Moreover, the prospects and challenges of advanced transdermal delivery strategies for treating dermatological disorders are summarized.

Psoriasis is an inflammatory skin disease. Microneedle (MN) patches can improve psoriasis treatment outcomes by increasing local drug content in the skin. As psoriasis frequently relapses, developing intelligent MN-based drug delivery systems with prolonged therapeutic drug levels and improved treatment efficiency is of great significance. Here, we designed detachable H2O2-responsive gel-based MN patches containing methotrexate (MTX) and epigallocatechin gallate (EGCG) by using EGCG as both cross-linkers for needle-composited materials and anti-inflammatory drugs. The gel-based MNs had dual-mode drug release kinetics, which quickly released MTX diffusively and sustainably released EGCG in an H2O2-responsive way. Compared with dissolving MNs, the gel-based MNs extended skin retention of EGCG, leading to prolonged reactive oxygen species (ROS) scavenging effects. The ROS-responsive MN patches that transdermally delivered antiproliferative and anti-inflammatory drugs improved treatment outcomes in both psoriasis-like and prophylactic psoriasis-like animal models.

Glucocorticoid-based creams are commonly used for treatments of psoriatic skin lesions while showing poor permeation because the thickened stratum corneum severely limits drug absorption. Although dissolving microneedle (DMN) patches have been employed in treating skin disease by virtue of their direct target to the lesion site, conventional DMN patches are generally fabricated from the water-soluble matrix, making them difficult to efficiently encapsulate hydrophobic glucocorticoids. Here, we develop a mechanically robust supramolecular DMN composed of hydroxypropyl β-cyclodextrin (HPCD) to effectively and uniformly load triamcinolone acetonide (TA). The TA-loaded HPCD DMN (TAMN) exhibits excellent mechanical performance that can easily pierce the thickened psoriasis lesions and deliver TA efficiently. Owing to the increased water solubility and bioavailability of TA after inclusion into HPCD, TAMN shows a superior in vitro inhibitory effect on immortalized human keratinocyte (HaCaT) cells. Importantly, the administration of TAMN twice a week effectively alleviates psoriatic signs and reduces the expression of Ki67, IL-23, and IL-17 in the ear lesions of imiquimod-induced psoriasis-like mice. This supramolecular DMN provides a promising strategy for the efficient treatment of psoriasis and other skin diseases, greatly broadens the applications of supramolecular materials in transdermal drug delivery, and widens the range of drugs in DMNs.

Lanthanide nanoparticles exhibit unique photophysical properties and thus emerge as promising second near-infrared (NIR-II) optical agents. However, the limited luminescence brightness hampers their construction of activatable NIR-II probes. Herein, we report the synthesis of dye-sensitized lanthanide nanoprobes (NaGdF4:Nd/ICG; indocyanine green (ICG)) and their further development for in vivo activatable imaging of hypochlorite (ClO–). Dye sensitization using ICG not only shifts the optimal doping concentration of Nd3+ from 5 to 20 mol % but also leads to a 5-fold NIR-II enhancement relative to the ICG-free counterpart. Mechanistic studies reveal that such a luminescence enhancement of NaGdF4:Nd at high Nd3+ concentration is ascribed to an alleviated cross-relaxation effect due to the broad absorption of ICG and faster energy transfer process. Taking advantage of dye oxidation, the nanoprobes enable activatable NIR-II imaging of hypochlorous acid (ClO–) in a drug-induced lymphatic inflammation mouse model. This work thus provides a simple, yet effective luminescence enhancement strategy for constructing lanthanide nanoprobes at higher activator doping concentration toward activatable NIR-II molecular imaging.

Tumor recurrence and metastasis are the main causes of cancer mortality; traditional chemotherapeutic drugs have severe toxicity and side effects in cancer treatment. To overcome these issues, here, we present a pH-responsive, self-destructive intelligent nanoplatform for magnetic resonance/fluorescence dual-mode image-guided mitochondrial membrane potential damage (MMPD)/photodynamic (PDT)/photothermal (PTT)/immunotherapy for breast cancer treatment with external near infrared (NIR) light irradiation. To do so, we construct multifunctional monolayer-layered double hydroxide (LDH) nanosheets (MICaP), co-loading indocyanine green (ICG) with ultrahigh loading content realized via electrostatic interactions, and calcium phosphate (Ca3(PO4)2) coating via biomineralization. Such a combined therapy design is featured by the outstanding biocompatibility and provokes immunogenic cell death (ICD) of tumors toward cancer immunotherapy. The active transport of excess Ca2+ released from pH-sensitive Ca3(PO4)2 can induce MMPD of tumor cells to minimize oxygen consumption in the tumor microenvironment (TME). The presence of ICG not only generates singlet oxygen (1O2) to induce apoptosis by photodynamic therapy (PDT) but also initiates tumor cell necrosis by photothermal therapy (PTT) under near-infrared (NIR) light radiation. Eventually, the immune response generated by MMPD/PDT/PTT greatly promotes a cytotoxic T lymphocyte (CTL) response that can limit tumor growth and metastasis. Both in vitro and in vivo studies indeed illustrate outstanding antitumor efficiency and outcomes. We anticipate that such precisely designed nanoformulations can contribute in a useful and advantageous way that is conducive to explore novel nanomedicines with notable values in antitumor therapy.