Hypertrophic scar (HS) is a common complication following burn injuries. The current evaluation of HS predominantly depends on subjective perception. This study aimed to investigate an objective biomarker for evaluating the proliferative activity and predicting susceptibility to post-burn HS. This retrospective cohort study enrolled 104 burn patients and 16 patients with post-burn HS. Serial serum Angiotensin II (AngII) levels were measured from admission to wound healing (371 measurements total). The primary outcome was the correlation between AngII levels and Vancouver Scar Scale (VSS) scores in patients not receiving anti-scar treatment. Propensity score matching was employed to balance confounding factors. In vitro experiments assessed AngII effects on fibroblast proliferation. The study found that serum AngII levels follow a dynamic trend from burn injury to wound healing, increasing 2–3 fold during proliferation and remodeling phases and remaining elevated post-healing, aligning with fibroblast activity. In vitro, AngII stimulated fibroblast proliferation. AngII levels correlated with age (P<0.05), being significantly higher in younger patients (200.61 vs 58.32 pg/ml), but not with burn index or sex. In patients with post-burn hypertrophic scars, AngII positively correlated with Vancouver Scar Scale scores (R2=0.797). A linear model using AngII to predict VSS scores was developed and validated. This first systematic characterization of post-burn serum AngII dynamics reveals that sustained AngII elevation may serve as a biomarker for active HS proliferation. AngII demonstrates potential for predicting individual HS susceptibility and identifying optimal timing for anti-scar therapy, providing a novel molecular basis for future personalized post-burn HS management research. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Psoriasis, an immune-mediated skin disorder, affects over 125 million people worldwide. Its primary manifestations include abnormal keratinocyte proliferation, epidermal inflammatory cell infiltration, and excessive neovascularization, and no fundamental intervention is currently available. Although siRNA therapy based on the RNA interference mechanism has opened a new avenue for the definitive treatment of psoriasis, its clinical application is limited by rapid degradation and low transfection efficiency, compounded by the skin's dense structure that hinders noninvasive transdermal delivery. To address these issues, we developed a transdermal siRNA delivery system using polyethylenimine (PEI) and Tween 80-modified transfersomes (TCPL) as carriers for NF-kappa B p65 siRNA (TCPL@siNF-kappa B). By embedding Tween 80 and PEI into the TCPL, the system achieves excellent proton buffering capacity, enabling multilayer encapsulation of siNF-kappa B at both the core and surface levels, effectively preventing its degradation in serum and enzymatic environments. This strategy resolves the molecular weight-dependent conflict between the transfection efficiency and toxicity of PEI, achieving a balanced performance. Moreover, TCPL exhibits ultradeformability, and this study demonstrates the advantages of Tween 80 in promoting transdermal gene transfection. TCPL@siNF-kappa B demonstrated efficient lysosomal escape and intracellular delivery via clathrin-mediated endocytosis and macropinocytosis, achieving high transfection efficiency. In vitro inflammatory models and a psoriasis-like mouse model confirmed that TCPL@siNF-kappa B enables efficient gene delivery through simple topical application, effectively silences NF-kappa B signaling, modulates the immune microenvironment, inhibits aberrant angiogenesis, and significantly alleviates psoriatic symptoms, while exhibiting excellent biocompatibility. Therefore, this study offers a promising non-invasive gene therapy strategy for psoriasis and other potential inflammatory skin disorders.

[This corrects the article DOI: 10.1016/j.bioactmat.2023.09.021.].

Nitric oxide (NO) as a promising therapeutic molecule for infection treatments is impeded by challenges of precise delivery and accumulation in treating deep tissue infections, such as osteomyelitis caused by methicillinresistant Staphylococcus aureus (MRSA). Herein, a bacterial-targeting liposome (MN@Mal-Lips) assembled by maltotriose (Mal)-modified cholesterol and lecithin was presented for synergistic NO/methicillin (MET) therapy of MRSA-infected osteomyelitis. MN@Mal-Lips were specifically internalized by MRSA via Mal transporters and thus targetedly accumulated at deep MRSA-infected site. Attributed to the capabilities of NO to induce biofilm dispersal and reverse bacterial resistance, the precisely delivered NO combined with MET facilitating efficient bacterial eradication by disrupting bacterial cell membrane and damaging bacterial DNA. Furthermore, MN@Mal-Lips relieved the local inflammation by potentiating the polarization of macrophages to M2-type while suppressing the M1-type. Meanwhile, MN@Mal-Lips promoted the proliferation, migration, and mineralization of osteoblast, as well as upregulated osteogenesis-related genes, thus repairing the bone tissue. Together, this bacterial-targeting NO-delivery liposome system offers an effective therapeutic strategy for clinical management of MRSA-induced osteomyelitis and may provide great possibilities in the development of NO therapy combating with deep tissue infections caused by drug-resistant bacteria.

The wound healing process in diabetic patients is often complex and prolonged, frequently complicated by persistent bacterial infections that can develop into multidrug-resistant infections, posing significant challenges for treatment. However, traditional hydrogel dressings often exhibit limited efficacy against complex wounds, primarily because therapeutic molecules are confined within the cross-linked matrix and exert nonselective antibacterial effects. This study developed a novel polyrotaxane-based hydrogel (FDS) against diabetic wounds complicated by drug-resistant bacterial infections. By assembling SNO-modified β-cyclodextrin onto the F-127DA copolymer backbone and copolymerized with dimethylamino propyl methacrylamide (DMAPMA), FDS hydrogel was endowed with conformational freedom of NO (Nitric Oxide) donor through rotatable and slidable motions and acid-responsive antibacterial properties simultaneously. This FDS hydrogel exhibited excellent antibacterial (both Staphylococcus aureus and methicillin-resistant S. aureus) and biofilm-dispersing effects, NO-enhanced angiogenesis, significantly reduced inflammatory response, and accelerated healing of chronic diabetic wounds in vitro and in vivo. By virtue of movable molecular anchoring facilitated NO delivery and microenvironment-activatable antibacterial activity, this research offers new hope for addressing the challenges of wound healing in diabetic patients accompanied by bacterial infections.

Progressive follicle and vascular atrophy, insufficient nutrient supply, and hormonal imbalance are direct causes of androgenic alopecia (AGA), limiting treatment options. Nitric oxide (NO) has demonstrated significant advantages in cell proliferation, vascular repair, and inflammation regulation. However, precise control of NO concentration and efficient utilization limit its clinical application for AGA treatment. To address this, we developed a near-infrared (NIR) light-triggered NO-releasing delivery system (Gel@L-Arg). The system uses Chlorin e6 (Ce6) grafted onto oxidized hyaluronic acid, reacting with L-Arg-loaded polyethyleneimine via Schiff base to form hyaluronic acid hydrogel. Under NIR light, Ce6 generates ROS, oxidizing L-Arg to release NO, after 5 min of irradiation, the NO concentration in Gel@L-Arg (1 %) is >1.5 times that in Gel@L-Arg (0.5 %), enabling on-demand release of NO. Gel@L-Arg (0.5 %) effectively promotes angiogenesis while significantly repairing damaged human dermal papilla cells (HDPCs), with cell viability reaching 131.6 +/- 4.6 %. In animal models, the system reduced inflammation (IL-6, TNF-alpha), enhanced nutrient supply (VEGF, CD31), regulated androgens, and improved the follicular microenvironment, effectively treating AGA. This hyaluronic acid hydrogel, combining NIR light-triggered release with gas therapy, offers a new strategy for the treatment of AGA with good biocompatibility, providing insight into controlled gas release therapies for disease treatment.

Transdermal drug delivery systems (TDDS) offer a noninvasive route for delivering active compounds directly to lesion sites while bypassing hepatic first-pass metabolism, thereby reducing systemic side effects and improving patient compliance. As such, TDDS have gained significant attention in disease treatment. However, the stratum corneum presents a major barrier to drug permeation due to its “brick-and-mortar” structure, limiting the effectiveness of transdermal strategies. Developing safe and efficient enhancement methods remains a major challenge. Among various drug delivery platforms, liposomal systems have attracted increasing interest owing to their nanoscale size, biocompatibility, high drug-loading capacity, and ability to protect drugs from enzymatic degradation. These carriers also interact favorably with skin lipids, enhancing drug penetration. Advances in nanotechnology have led to the development of novel liposomal formulations such as ethosomes, transfersomes, niosomes, and pharmacosomes, each tailored to address specific therapeutic needs. This review summarizes recent progress in liposome-based TDDS for both skin and systemic diseases, highlighting their mechanisms of action, therapeutic benefits, and clinical translation potential. Additionally, it explores future directions and ongoing challenges, aiming to provide a reference for advancing liposomal technologies in transdermal drug delivery.

Long-term exposure to ultraviolet (UV) radiation can damage human skin, resulting in photodamage. Repairing photodamaged skin has been a major focus of research in recent years. Extensive research has shown that human umbilical cord mesenchymal stem cell-derived exosomes (Exo) possess anti-inflammatory, pro-angiogenic, and wound healing properties, holding great potential for treating skin damage. However, due to the limitations of exosomes alone, such as poor transdermal penetration, instability, and low utilization, there is an urgent need for new delivery strategies. We designed a hybrid nanovesicle (HL@Exo) by combining ultrasonic incubation with membrane extrusion to fuse Exo with HL. HL@Exo capitalizes on the advantages of liposomal carriers and the permeation-enhancing properties of hyaluronic acid to effectively facilitate transdermal delivery of Exo. The successful fusion of HL@Exo and its skin penetration were verified by methods such as fluorescent labeling, western blotting, Transwell assays, and in vivo imaging. In vitro studies on photodamaged keratinocytes and endothelial cells demonstrated HL@Exo ability to promote cell proliferation, repair, angiogenesis, and reduce inflammation. In a laser-induced skin photodamage model, HL@Exo enhanced collagen regeneration, accelerated wound healing, and demonstrated significant anti-inflammatory effects, indicating its potential as a non-invasive treatment and offering a novel strategy for the clinical application of Exo.

Minoxidil (Mi) is currently one of the most commonly used drugs for the treatment of hair loss in clinical settings. It works by accelerating blood flow around the hair follicles, enhancing local oxygen and nutrient supply, thereby promoting hair growth. However, traditional formulations of Mi have a short residence time on the skin, are prone to causing allergic reactions, scaling, and may even induce systemic hypertrichosis as side effects. This highlights the urgent need for the development of more efficient and safer delivery systems to improve its therapeutic efficacy. In previous studies, our team developed a high molecular weight hyaluronic acid-based delivery platform (HL) with excellent skin penetration, anti-inflammatory properties, and tissue repair capabilities. In this study, we used the HL delivery material as a carrier for Mi and developed a Mi delivery system with high drug encapsulation efficiency and good biological safety-HL@Mi. This delivery system encapsulates Mi within HL using techniques such as reverse evaporation, high-speed homogenization, and microjet high-pressure methods. Fluorescent labeling and high-performance liquid chromatography (HPLC) were employed to confirm that HL@Mi significantly enhanced the skin penetration and retention of Mi, effectively improving the local bioavailability of Mi. In vitro experiments, HL@Mi significantly reduced the cytotoxicity of Mi, while optimizing the hair follicle microenvironment by promoting angiogenesis and regulating the expression of IL-6, MMP3, and β-catenin genes associated with hair follicle function. In an established androgenetic alopecia animal model, HL@Mi significantly downregulated the expression of inflammatory factors such as IL-6, TNF-α, and TGF-β1 in the skin, while upregulating Ki67 expression in the hair follicle tissue, thereby accelerating hair growth and effectively improving hair loss symptoms. Moreover, HL@Mi exhibited good biocompatibility and safety. In summary, HL@Mi, as a novel transdermal delivery system, not only provides a more efficient and safer clinical alternative for Mi in the treatment of androgenetic alopecia, but also offers valuable technical insights for other local drug delivery strategies.

Photodamage is one of the most common causes of skin injury. High molecular weight hyaluronic acid (HHA) has shown immense potential in the treatment of skin photodamage by virtue of its anti-inflammatory, reparative, and antioxidative properties. However, due to its large molecular structure of HHA, HHA solution could only form a protective film on the skin surface in conventional application, failing to effectively penetrate the skin, which necessitates the development of new delivery strategies. Liposomes, with a structure similar to biological membranes, have garnered extensive attention as transdermal drug delivery carriers because of their advantages in permeability, dermal compatibility, and biosafety. Herein, we have developed a HHA-liposome transdermal system (HHL) by embedding HHA into the liposome structure using reverse evaporation, high-speed homogenization, and micro-jet techniques. The effective penetration and long-term residence of HHA in skin tissue were multidimensionally verified, and the kinetics of HHA in the skin were extensively studied. Moreover, it was demonstrated that HHL significantly strengthened the activity of human keratinocytes and effectively inhibits photo-induced cellular aging in vitro. Furthermore, a murine model of acute skin injury induced by laser ablation was established, where the transdermal system showed significant anti-inflammatory and immunosuppressive properties, promoting skin proliferation and scar repair, thereby demonstrating immense potential in accelerating skin wound healing. Meanwhile, HHL significantly ameliorated skin barrier dysfunction caused by simulated sunlight exposure, inhibited skin erythema, inflammatory responses, and oxidative stress, and promoted collagen expression in a chronic photodamage skin model. Therefore, this transdermal delivery system with biocompatibility represents a promising new strategy for the non-invasive application of HHA in skin photodamage, revealing the significant potential for clinical translation and broad application prospects.Statement of SignificanceThe transdermal system utilizing hyaluronic acid-based liposomes enhances skin permeability and retains high molecular weight hyaluronic acid (HHL). In vitro experiments with human keratinocytes demonstrate significant skin repair effects of HHL and its effective inhibition of cellular aging. In an acute photodamage model, HHL exhibits stronger anti-inflammatory and immunosuppressive properties, promoting skin proliferation and scar repair. In a chronic photodamage model, HHL significantly improves skin barrier dysfunction, reduces oxidative stress induced by simulated sunlight, and enhances collagen expression.

Androgenic alopecia (AGA) is a prevalent progressive hair loss condition. The main therapeutic drug, minoxidil, is limited by its poor efficacy and side effects such as contact dermatitis and hypertrichosis. Nitric oxide (NO), an endothelial-derived relaxing factor, promotes angiogenesis and accelerates blood flow, enhancing nutrient supply similar to minoxidil. Accordingly, we utilized a poly(vinyl alcohol) film (PVA) loaded with hyaluronic acid (HA) liposomes to construct a multistage transdermal NO delivery system (PVA@HL/NONOate) for the treatment of AGA. The HA liposomes provided efficient NO loading and extended release, while the PVA film improved skin penetration and sustained NO release, increasing NO bioavailability. Low-concentration NO effectively enhanced hair follicle vitality and repaired blood vessels. Mechanistically, low-concentration NO could treat AGA mainly by regulating the HIF-1 signaling pathway to promote angiogenesis, reducing inflammation by downregulating the expression of TNFRSF9 and IL-6, repairing hair follicles by downregulating the expression of genes in the CXCL5-IL-17 inflammatory axis.

Hyperuricemia-related diabetic wounds are notoriously difficult to treat due to elevated uric acid (UA) levels, excessive reactive oxygen species (ROS), and chronic inflammation. Current therapies often fail to address these underlying causes, underscoring the need for innovative approaches that not only clear UA but also mitigate inflammation and promote tissue regeneration. In this study, we developed a polyrotaxane-based microsphere (HPR MS) system conjugated with 4,5-diamino-2-thiouracil (DT) to achieve high-affinity UA clearance without increasing cytotoxicity. By leveraging the molecular motility of the polyrotaxane structure, featuring β-cyclodextrin (β-CD) shuttles along the F-127 axis, we significantly improved the molecular recognition between DT and UA for enhanced UA absorption efficiency. In vitro experiments confirmed that HPR/DT MS rapidly reduced UA levels compared to control groups. Using a type 2 diabetic wound model, HPR/DT MS treatment effectively reduced UA levels, suppressed COX-2 expression, and transformed the immune microenvironment from a pro-inflammatory to a regenerative state in vivo. This was accompanied by enhanced M2 macrophage polarization, angiogenesis, and improved blood perfusion, resulting in accelerated wound healing. Overall, these findings highlight HPR/DT MS as a promising therapeutic strategy for hyperuricemia-related diabetic wounds, targeting the core pathological factors to improve wound repair.

This work provides a nanodelivery platform with excellent biosafety and controlled release of a donor, while enhancing the therapeutic efficacy of nitric oxide gas therapy synergized with photothermal therapy for nasopharyngeal carcinoma.

Bacterial infections, especially those from drug-resistant strains, pose a significant threat to healing diabetic skin injuries, with current treatments being intricated and often unsatisfactory. Inspired by octopuses, a biomimetic material using alpha-cyclodextrin (alpha-CD) and polyethylene glycol (PEG) assembled with graphene oxide end-capped polyrotaxanes (GO-PR) is developed, where alpha-CD mimics the flexible tentacles of an octopus. Further, alpha-CD is cationically modified with polyethyleneimine (PEI) to resemble octopus suction cups, creating GO-PRP, which effectively captures and adheres to bacteria. Importantly, to emulate an octopus's ink defense, GO-PRP is used as a carrier for nitric oxide (NO), resulting in GO-PRP/NONOate. Utilizing the photothermal conversion of GO, near-infrared light exposure triggers rapid heating and NO release, providing efficient antibacterial activity and biofilm dispersion, significantly reducing inflammation in diabetic skin injuries in type I rats. During wound healing, sustained NO release promotes vascular endothelial growth factor production and blood vessel regeneration, enhancing collagen formation and shortening the healing time for diabetic skin infections. Thus, octopus-inspired GO-PRP/NONOate emerges as a novel biomaterial for treating drug-resistant bacterial infections in diabetic wounds in the biomedical field. Inspired by octopus entangling prey, a biomimetic material with polyrotaxane chains as flexible tentacles and cationic cyclodextrins as suction cups is created for bacterial capture. Mimicking octopuses' rapid ink release to paralyze prey, burst NO release is triggered by NIR for antibacterial action synergizing with PTT, followed by the slow release for repair, reducing the inflammation cycle of DSI. image

Androgenetic alopecia (AGA) is a common clinical condition, affecting over 200 million people globally each year. For decades, Minoxidil (Mi) tincture has been the primary treatment for this disease, but its low utilization rate and significant side effects necessitate new therapeutic strategies. Nitric oxide (NO) is a signaling molecule in various physiological processes, including vasodilation, immune responses, and cell proliferation. Herein, we constructed a hyaluronic acid liposome (HL) complex as a novel transdermal delivery system (HL@Mi/NONOate) for NO and Mi, which displayed promising transdermal and hair-regrowth effects. In-depth mechanistic studies revealed three potential pathways of the synergistic AGA therapy. First, NO promoted capillary dilation and accelerated blood flow, thus achieving efficient penetration of Mi. Due to the structural advantage of liposomes, the residence time of the Mi in the skin was prolonged. Moreover, HL@Mi/NONOate promoted cell proliferation and angiogenesis, and upregulated the expression of regulatory factors involved in follicle stem cell differentiation. In the AGA model, HL@Mi/NONOate down-regulated the expression of inflammatory factors, inhibiting the inflammation of follicle and improving the microenvironment of hair regrowth. Concurrently, HL@Mi/NONOate upregulated the expression of Ki67 and PCNA proteins in follicle tissues, inducing follicle regeneration and development, ultimately achieving the synergistic multimodal AGA therapy.

Polymeric systems that provide cationic charges or biocide-release therapeutics are used to treat the bacteria-infected wound. However, most antibacterial polymers based on topologies with restricted molecular dynamics still do not satisfy the clinical requirements due to their limited antibacterial efficacy at safe concentrations in vivo. Here a NO-releasing topological supramolecular nanocarrier with rotatable and slidable molecular entities is reported to provide conformational freedom to promote the interactions between the carrier and the pathogenic microbes, hence greatly improving the antibacterial performance. With improved contacting-killing and efficient delivery of NO biocide from the molecularly dynamic cationic ligand design, the NO-loaded topological nanocarrier achieves excellent antibacterial and anti-biofilm effects via destroying the bacterial membrane and DNA. MRSA-infected rat model is also brought out to demonstrate its wound-healing effect with neglectable toxicity in vivo. Introducing flexible molecular motions into therapeutic polymeric systems is a general design to enhance the healing of a range of diseases.

The low permeability of antifungal agents to fungal biofilms, which allows the continued survival of the fungus inside, is a key issue that makes fungal infections difficult to cure. Inspired by the unique dynamic molecule motion properties of the polyrotaxane (PR) nanomedicine, herein, a dynamic delivery system Clo@mPRP/NONOate was fabricated by co-loading nitric oxide (NO) and the antifungal drug clotrimazole (Clo) onto the α-cyclodextrin (α-CD) PR modified mesoporous polydopamine (mPDA) nanoparticles, in which pentaethylenehexamine (PEHA) was grafted to α-CDs. The cationic α-CDs endowed this dynamic NO/Clo codelivery system with the ability to effectively attach to fungal biofilms through electrostatic interaction, while the introduction of PRs with flexible molecule motion (slide and rotation of CDs) enhanced the permeability of nanoparticles to biofilms. Meanwhile, NO could effectively inhibit the formation of fungal hyphae, showing an dissipating effect on mature biofilms, and could be further combined with Clo to completely eradicate fungi inside the biofilms. In addition, the dynamic system Clo@mPRP/NONOate could efficiently and synergistically eliminate planktonic Candida albicans (C. albicans) in a safe and no toxic side effect manner, and effectively cured C. albicans-induced vaginal infection in mice. Therefore, this dynamic NO/Clo codelivery system provided an effective solution to the clinical treatment of C. albicans-induced vaginal infection, and the application prospect could even be extended to other microbial infectious diseases. STATEMENT OF SIGNIFICANCE: A dynamic codelivery system based on cationized cyclodextrin polyrotaxane combining nitric oxide and antifungal drugs clotrimazole was prepared to deal with the issue of clinical fungal biofilm infection. This dynamic codelivery system could be attached to the Candida albicans biofilms and penetrate into biofilm via flexible molecular mobility to effectively eradicate the fungi. This dynamic codelivery system could synergistically and efficiently eliminate planktonic-state Candida albicans, but did not show significant cytotoxicity to normal somatic cells.