Over 15% of acne patients manifest moderate to severe clinical presentations, accompanied with bacterial infection, long-term inflammatory responses, dysregulated lipid metabolism, and post-acne skin atrophy. Although microneedles (MNs) represent an effective transdermal drug delivery system for acne treatment, the therapeutic effects on the restoration of dysregulated lipid metabolism and the prevention of atrophic acne scars are still lacking. Herein, we develop proteoglycan-mimetic comb polymer (HMC)-based dissolving microneedles (HMC-PEP MNs) with encapsulation of therapeutic peptides. This system effectively targets the acne pathophysiological pathways involving bacterial colonization, lipid dysregulation, chronic inflammation and impaired tissue repair. Specifically, HMC enables sustained release of antimicrobial and anti-inflammatory peptides via multiple non-covalent interactions. HMC-PEP MNs display significant efficacy via eradicating Cutibacterium acnes infection, suppressing pro-inflammatory mediator expression, and reducing the TREM2/M2 macrophage ratio. Integrated transcriptomic and metabolomic analysis reveals that HMC-PEP MNs effectively regulate cholesterol and linoleic acid metabolism, inhibit pro-inflammatory signaling transduction, and reduce keratinocyte proliferation and differentiation by inhibiting the IGF1/IGF1R/PI3K/AKT/mTOR signaling pathway. Interestingly, HMC-PEP MNs also promote collagen synthesis and ameliorate fibroblast dysfunction, thereby preventing the formation of post-acne dermal atrophy. This study presents an effective therapeutic strategy for acne and elucidates the underlying mechanisms of HMC-PEP MNs, demonstrating considerable promise for clinical translation.

Near-infrared (NIR)-II fluorescence imaging-guided photodynamic therapy (PDT) has shown great potential for precise diagnosis and treatment of tumors in deep tissues; however, its performance is severely limited by the undesired aggregation of photosensitizers and the competitive relationship between fluorescence emission and reactive oxygen species (ROS) generation. Herein, we report an example of an anionic pentamethine cyanine (C5T) photosensitizer for high-performance NIR-II fluorescence imaging-guided PDT. Through the counterion engineering approach, a triphenylphosphine cation (Pco) modified with oligoethylene glycol chain is synthesized and adopted as the counterion of C5T, which can effectively suppress the excessive and disordered aggregation of the resulting C5T-Pco by optimizing the dye amphipathicity and enhancing the cyanine-counterion interactions. Dynamic tuning of fluorescence characteristics and ROS generation is achieved at the aggregate level, resulting in an impressive type I ROS generation under 760 nm light irradiation, accompanied by efficient NIR-II fluorescence emission excited at 808 nm. As a result, excitation wavelength selective NIR-II fluorescence imaging-guided PDT has been successfully demonstrated for tumor diagnosis and therapeutics of female mice. Near-infrared-II fluorescence imaging-guided photodynamic therapy is hindered by the undesired aggregation of photosensitizers and the competition between fluorescence emission and reactive oxygen species generation. Here, the authors report an anionic pentamethine-based photosensitizer enabling excitation wavelength-selective fluorescence imaging-guided photodynamic therapy.

The immunomodulatory efficacy of current psoriasis biological therapies is hindered by their limited ability to scavenge multiple cytokines, inefficient delivery to specific inflamed skin regions, and potential side effects. Upon analyzing samples from both patients and mice, we identify a significant increase in type IV collagen within the extracellular matrix (ECM) of psoriatic skin. Thus, we report the microneedle (MN) delivery of type IV collagen targeting peptide-modified dual-cell membrane biomimetic nanodecoys (CRHM@lip) with multiple cytokines scavenging ability for treating psoriasis. The CRHM@lip can scavenge both tumor necrosis factor-α (TNF-α) and interleukin (IL)-17. Upon MN delivery, the nanodecoys target ECM and exhibit skin retention for over 120 h. The treatment by CRHM@lip-integrated MNs reduces skin thickness in mice by 57.9% and shows decreased levels of TNF-α, IL-17, IL-23, and interferon (IFN)-γ in skin sections compared to the psoriasis group. Additionally, the CRHM@lip treatment reduces the CD4+ T cells, M1 macrophages, and dendritic cells in the spleen, and suppresses various inflammatory mediators in serum, significantly demonstrating immunological microenvironmental suppression. Compared to systemic administration routes, MN delivery improves treatment outcomes. No noticeable adverse effects on hepatic and renal functions are observed in mice after treatment. This approach enhances the effectiveness of biological therapies and has the potential for translation.

The precise control of the assembly structure and size of gold nanoclusters (AuNCs) can potentially amplify their near-infrared II (NIR-II) fluorescence imaging and targeting properties. However, the conventional electrostatic assembly of AuNCs and charged molecules faces challenges in balancing the inherent electrostatic repulsions among charged units and regulating the diffusion of assembly units. These difficulties limit precise control over assembly size and structure, along with limited options for coassembled molecules, thereby restricting imaging properties and targeting capability. To circumvent this challenge, we developed a reverse emulsion-confined electrostatic assembly method. This technique efficiently constructs AuNC nanoassemblies with diverse coassembled molecules, allowing for the fine-tuning of assembly size and structure, including both core-satellite and homogeneous AuNC nanoassemblies. The development of two distinct nanoassemblies can be partially attributed to the varying diffusive rates of AuNCs or the AuNCs/polymer complex within the fused emulsion droplets. This variance arises from steric hindrances encountered during the emulsion fusion process. Interestingly, core-satellite nanoassemblies exhibit the strongest NIR-II fluorescence enhancement. Finally, the introduction of a hyaluronic acid coating on the surfaces of nanoassemblies with varying sizes enables the nanoprobes to achieve enhanced lymph node imaging through size modulation and macrophage targeting, which are used for surgical navigation to remove lymph node metastases. We envision that this self-assembly strategy can be extended to a wide range of electrostatic assembly systems for the development of multicomponent functional materials.

The stratum corneum (SC) and cell membrane are two major barriers that hinder the therapeutic outcomes of transdermal drug delivery for the treatment of skin diseases. While microneedles (MNs) can efficiently penetrate the SC to deliver nanomedicines, the optimization of physicochemical properties of nanomedicines in MNs to enhance their in vivo cellular delivery efficiency remains unclear. Here, how the size and surface charge of drug-loaded liposomes in MNs influence the retention time and cellular delivery in psoriatic skin is systematically investigated. The results indicate that while 100 nm negatively-charged liposomes in MNs show higher cellular uptake in vitro, 250 and 450 nm liposomes could enhance skin retention and the long-term in vivo cellular delivery efficiency of drugs. Moreover, 250 nm cationic liposomes with a stronger positive charge show an extraordinarily long skin retention time of 132 h and significantly higher in vivo cellular internalization. In the treatment study, dexamethasone (dex)-loaded cationic liposomes-integrated MNs show better therapeutic outcomes than dex-loaded anionic liposomes-integrated MNs in a psoriasis-like animal model. The design principles of liposomes in MN drug delivery systems explored in the study hold the potential for enhancing the therapeutic outcomes of psoriasis and are instrumental for successful translation.

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.

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.

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.

14 Skin diseases are the fourth leading cause of nonfatal and chronic skin diseases, 15 acting as a global burden and affecting the world economy. Skin diseases severely 16 impact the patients’ quality of life and have influenced their physical and mental state. 17 Treatment of these skin disorders with conventional methods shows a lack of 18 therapeutic efficacy, long treatment duration, recurrence of the condition, and systemic 19 side effects due to improper drug delivery. However, these pitfalls can be overcome 20 with the applications of advanced nanocarrier- and microneedle (MN)-based 21 transdermal drug delivery strategies that provide efficient site-specific drug delivery at 22 the target site. These advanced transdermal drug delivery strategies can be more 23 effective than other drug administration routes by avoiding first-pass metabolism, 24 enhancing the drug concentration in local skin lesions, and reducing systemic toxicity. 25 Compared with traditional transdermal delivery methods, nanocarrier- or MN-based 26 drug delivery systems are painless, noninvasive, or minimum-invasive and require no 27 expensive equipment. More importantly, they can introduce more advanced functions, 28 including increased skin penetration efficiency, controlled drug release rates, enhanced 29 targeting abilities, and theranostic functions. Here, the emergence of versatile advanced 30 transdermal drug delivery systems for the transdermal delivery of various drugs is 31 reviewed, focusing on the design principles, advantages, and considerations of 32 nanocarrier- and MN-based transdermal drug delivery strategies and their applications 33 in treating diverse skin diseases, including psoriasis, dermatitis, melanoma, and other 34 skin diseases. Moreover, the prospects and challenges of advanced transdermal delivery 35 strategies for treating dermatological disorders are summarized. 36