PROTAC Degraders of Androgen Receptor-Integrated Dissolving Microneedles for Androgenetic Alopecia and Recrudescence Treatment via Single Topical Administration.

Androgenetic alopecia (AGA) is a transracial and cross-gender disease worldwide with a youth-oriented tendency, but it lacks effective treatment. The binding of androgen receptor (AR) and androgen plays an essential role in the occurrence and progression of AGA. Herein, novel proteolysis targeting chimera degrader of AR (AR-PROTAC) is synthesized and integrated with dissolving microneedles (PROTAC-MNs) to achieve AR destruction in hair follicles for AGA treatment. The PROTAC-MNs possess adequate mechanical capabilities for precise AR-PROTAC delivery into the hair follicle-residing regions for AR degradation. After applying only once topically, the PROTAC-MNs achieve an accelerated onset of hair regeneration as compared to the daily application of the first-line topical drug minoxidil. Intriguingly, PROTAC-MNs via single administration still realize superior hair regeneration in AGA recrudescence, which is the major drawback of minoxidil in clinical practice. With the degradation of AR, the PROTAC-MNs successfully regulate the signaling cascade related to hair growth and activate hair follicle stem cells. Furthermore, the PROTAC-MNs do not cause systemic toxicity or androgen deficiency-related chaos in vivo. Collectively, these AR-degrading dissolving microneedles with long-lasting efficacy, one-step administration, and high biocompatibility provide a great therapeutic potential for AGA treatment.

Conditioned media-integrated microneedles for hair regeneration through perifollicular angiogenesis.

Androgenetic alopecia (AGA), the most prevalent type of hair loss in clinic, is induced partly by insufficient perifollicular vascularization. Here we designed a dissolvable microneedles (MNs) patch that was loaded with conditioned media (CM) derived from hypoxia-pretreated mesenchymal stem cells, which contained elevated HIF-1α. The CM-integrated MNs patch (designated as CM-MNs) can puncture the stratum corneum and deliver the pro-angiogenic factors directly into skin in a one-step and minimally invasive manner. Meanwhile, the administration of CM-MNs induced a certain mechanical stimulation on the skin, which can also promote neovascularization. With the combined effects of the pro-angiogenic factors in CM and the mechanical stimulation induced by MNs, CM-MNs successfully boosted perifollicular vascularization, and activated hair follicle stem cells, thereby inducing notably faster hair regeneration at a lower administration frequency on AGA mouse model compared with minoxidil. Furthermore, we proved that the inhibition of perifollicular angiogenesis restrained the awakening of hair follicle stem cells, elucidating the tight correlation between perifollicular angiogenesis and the activation of hair follicle stem cells. The innovative integration of CM and MNs holds great promise for clinical AGA treatment and indicates that boosting angiogenesis around hair follicles is an effective strategy against AGA.

Hair follicle-targeting drug delivery strategies for the management of hair follicle-associated disorders.

The hair follicle is not only a critical penetration route in percutaneous absorption but also has been recognized to be a target for hair follicle-associated disorders, such as androgenetic alopecia (AGA) and acne vulgaris. Hair follicle-targeting drug delivery systems allow for controlled drug release and enhance therapeutic efficacy with minimal side effects, exerting a promising method for the management of hair follicle-associated dysfunctions. Therefore, they have obtained much attention in several fields of research in recent years. This review gives an overview of potential follicle-targeting drug delivery formulations currently applied based on the particularities of the hair follicles, including a comprehensive assessment of their preclinical and clinical performance.

A Facile Low-Dose Photosensitizer-Incorporated Dissolving Microneedles-Based Composite System for Eliciting Antitumor Immunity and the Abscopal Effect.

Nanomedicine-based photodynamic therapy (PDT) for melanoma treatment has attracted great attention. However, the complex design of polymer nanoparticles and high doses of photosensitizers used in intravenous injections (for sufficient accumulation of drugs in tumor lesions) pose a huge challenge to the commercialization and further clinical application. Herein, we fabricated the carrier-free nanoassemblies of a chlorin e6 (L-Ce6 NAs)-integrated fast-dissolving microneedles patch (L-Ce6 MNs) enriching only about 3 µg of Ce6 in the needle tips via a facile fabrication method. The L-Ce6 MNs had sufficient mechanical strength to penetrate the skin and facilitated the transportation of L-Ce6 NAs to a depth of 200-500 µm under the skin, thereby achieving efficient and accurate drug delivery to tumor lesions. In a xenograft mouse melanoma model, the L-Ce6 MNs-based PDT with low dose of Ce6 (0.12 mg/kg) exerted efficient ablation of the primary lesions in situ through reactive oxygen species (ROS) generation. More importantly, a significant abscopal effect was also elicited by activating immunogenic cell death (ICD) and releasing danger-associated molecular patterns (DAMPs), which in turn promoted dendritic cells (DCs) maturation and the subsequent antigen presentation, thereby facilitating the T-cell-mediated immune response without synergetic immunotherapies. Collectively, our findings indicate the facile, controllable, and fast-dissolving microneedles patch with a low dose of photosensitizers presented great therapeutic potential for enhanced photoimmunotherapy.

Ceria Nanozyme-Integrated Microneedles Reshape the Perifollicular Microenvironment for Androgenetic Alopecia Treatment.

Androgenetic alopecia (AGA) is highly prevalent in current society but lacks effective treatments. The dysregulation of the hair follicle niche induced by excessive reactive oxygen species (ROS) and insufficient vascularization in the perifollicular microenvironment is the leading cause of AGA. Herein, we designed a ceria nanozyme (CeNZ)-integrated microneedles patch (Ce-MNs) that can alleviate oxidative stress and promote angiogenesis simultaneously to reshape the perifollicular microenvironment for AGA treatment. On the basis of the excellent mechanical strength of Ce-MNs, the encapsulated CeNZs with catalase- and superoxide-mimic activities can be efficiently delivered into skin to scavenge excessive ROS. Moreover, the mechanical stimulation induced by the administration of MNs can remodel the microvasculature in the balding region. Compared with minoxidil, a widely used clinical drug for AGA treatment, Ce-MNs exhibited accelerated hair regeneration in the AGA mouse model at a lower administration frequency without inducing significant skin damage. Consequently, such a safe and perifollicular microenvironment-shaping MNs patch shows great potential for clinical AGA treatment.