Nanodelivery Systems for Topical Management of Skin Disorders.

Topical drug delivery has inherent advantages over other administration routes. However, the existence of stratum corneum limits the diffusion to small and lipophilic drugs. Fortunately, the advancement of nanotechnology brings along opportunities to address this challenge. Taking the unique features in size and surface chemistry, nanocarriers such as liposomes, polymeric nanoparticles, gold nanoparticles, and framework nucleic acids have been used to bring drugs across the skin barrier to epidermis and dermis layers. This article reviews the development of these formulations and focuses on their applications in the treatment of skin disorders such as acne, skin inflammation, skin infection, and wound healing. Existing hurdles and further developments are also discussed.

Iridium(III) Complex-Derived Polymeric Micelles with Low Dark Toxicity and Strong NIR Excitation for Phototherapy and Chemotherapy.

Iridium(III) complexes are potent candidates for photodynamic therapy. However, their clinical usage is impeded by their poor water solubility, high dark toxicity, and negligible absorption in near-infrared region (NIR region). Here, it is proposed to solve these challenges by developing an iridium(III) complexe-based polymeric micelle system. This system is self-assembled using an iridium(III) complex-containing amphiphilic block polymer. The upconversion nanoparticles are included in the polymeric micelles to permit NIR excitation. Compared with the nonformulated iridium(III) complexes, under NIR stimulation, this polymeric micelle system exhibits higher 1 O2 generation efficiency, negligible dark toxicity, excellent tumor-targeting ability, and synergistic phototherapy-chemotherapy effect both in vitro and in vivo.

Surface protein engineering increases the circulation time of a cell membrane-based nanotherapeutic.

Mammalian cell membranes are often incompatible with chemical modifications typically used to increase circulation half-life. Using cellular nanoghosts as a model, we show that proline-alanine-serine (PAS) peptide sequences expressed on the membrane surface can extend the circulation time of a cell membrane derived nanotherapeutic. Membrane expression of a PAS 40 repeat sequence decreased protein binding and resulted in a 90% decrease in macrophage uptake when compared with non-PASylated controls (P ≤ 0.05). PASylation also extended circulation half-life (t1/2 = 37 h) compared with non-PASylated controls (t1/2 = 10.5 h) (P ≤ 0.005), resulting in ~7-fold higher in vivo serum concentrations at 24 h and 48 h (P ≤ 0.005). Genetically engineered membrane expression of PAS repeats may offer an alternative to PEGylation and provide extended circulation times for cellular membrane-derived nanotherapeutics.

Robust Colloidal Nanoparticles of Pyrrolopyrrole Cyanine J-Aggregates with Bright Near-Infrared Fluorescence in Aqueous Media: From Spectral Tailoring to Bioimaging Applications.

Colloidal nanoparticles (NPs) containing near-infrared-fluorescent J-aggregates (JAGGs) of pyrrolopyrrole cyanines (PPcys) stabilized by amphiphilic block co-polymers were prepared in aqueous medium. JAGG formation can be tuned by means of the chemical structure of PPcys, the concentration of chromophores inside the polymeric NPs, and ultrasonication. The JAGG NPs exhibit a narrow emission band at 773 nm, a fluorescence quantum yield comparable to that of indocyanine green, and significantly enhanced photostability, which is ideal for long-term bioimaging.

Nanosensors for Continuous and Noninvasive Monitoring of Mesenchymal Stem Cell Osteogenic Differentiation.

Assessing mesenchymal stem cell (MSC) differentiation status is crucial to verify therapeutic efficacy and optimize treatment procedures. Currently, this involves destructive methods including antibody-based protein detection and polymerase chain reaction gene analysis, or laborious and technically challenging genetic reporters. Development of noninvasive methods for real-time differentiation status assessment can greatly benefit MSC-based therapies. This report introduces a nanoparticle-based sensing platform that encapsulates two molecular beacon (MB) probes within the same biodegradable polymeric nanoparticles. One MB targets housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal reference, while another detects alkaline phosphatase (ALP), a functional biomarker. Following internalization, MBs are gradually released as the nanoparticle degrades. GAPDH MBs provide a stable reference signal throughout the monitoring period (18 days) regardless of differentiation induction. Meanwhile, ALP mRNA undergoes well-defined dynamics with peak expression observed during early stages of osteogenic differentiation. By normalizing ALP-MB signal with GAPDH-MB, changes in ALP expression can be monitored, to noninvasively validate osteogenic differentiation. As proof-of-concept, a dual-colored nanosensor is applied to validate MSC osteogenesis on 2D culture and polycaprolactone films containing osteo-inductive tricalcium phospate.

Synergism of Water Shock and a Biocompatible Block Copolymer Potentiates the Antibacterial Activity of Graphene Oxide.

Graphene oxide (GO) is promising in the fight against pathogenic bacteria. However, the antibacterial activity of pristine GO is relatively low and concern over human cytotoxicity further limits its potential. This study demonstrates a general approach to address both issues. The developed approach synergistically combines the water shock treatment (i.e., a sudden decrease in environmental salinity) and the use of a biocompatible block copolymer (Pluronic F-127) as a synergist co-agent. Hypoosmotic stress induced by water shock makes gram-negative pathogens more susceptible to GO. Pluronic forms highly stable nanoassemblies with GO (Pluronic-GO) that can populate around bacterial envelopes favoring the interactions between GO and bacteria. The antibacterial activity of GO at a low concentration (50 µg mL(-1) ) increases from <30% to virtually complete killing (>99%) when complemented with water shock and Pluronic (5 mg mL(-1) ) at ≈2-2.5 h of exposure. Results suggest that the enhanced dispersion of GO and the osmotic pressure generated on bacterial envelopes by polymers together potentiate GO. Pluronic also significantly suppresses the toxicity of GO toward human fibroblast cells. Fundamentally, the results highlight the crucial role of physicochemical milieu in the antibacterial activity of GO. The demonstrated strategy has potentials for daily-life bacterial disinfection applications, as hypotonic Pluronic-GO mixture is both safe and effective.

Stimuli-responsive liposomes for the delivery of nucleic acid therapeutics.

Nucleic acid therapeutics (NATs) are valuable tools in the modulation of gene expression in a highly specific manner. So far, NATs have been actively pursued in both pre-clinical and clinical studies to treat diseases such as cancer, infectious and inflammatory diseases. However, the clinical application of NATs remains a considerable challenge owing to their limited cellular uptake, low biological stability, off-target effect, and unfavorable pharmacokinetics. One concept to address these issues is to deliver NATs within stimuli-responsive liposomes, which release their contents of NATs upon encountering environmental changes such as temperature, pH, and ion strength. In this case, before reaching the targeted tissue/organ, NATs are protected from degradation by enzymes and immune system. Once at the area of interest, localized and targeted delivery can be achieved with minimal influence to other parts of the body. Here, we discuss the latest developments and existing challenges in this field. FROM THE CLINICAL EDITOR: Nucleic acid therapeutics have been shown to enhance or eliminate specific gene expression in experimental research. Unfortunately, clinical applications have so far not been realized due to problems of easy degradation and possible toxicity. The use of nanosized carriers such as liposomes to deliver nucleic acids is one solution to overcome these problems. In this review article the authors describe and discuss the potentials of various trigger-responsive "smart" liposomes, with a view to help other researchers to design better liposomal nucleic acid delivery systems.

Tracking mesenchymal stem cells with iron oxide nanoparticle loaded poly(lactide-co-glycolide) microparticles.

Monitoring the location, distribution and long-term engraftment of administered cells is critical for demonstrating the success of a cell therapy. Among available imaging-based cell tracking tools, magnetic resonance imaging (MRI) is advantageous due to its noninvasiveness, deep penetration, and high spatial resolution. While tracking cells in preclinical models via internalized MRI contrast agents (iron oxide nanoparticles, IO-NPs) is a widely used method, IO-NPs suffer from low iron content per particle, low uptake in nonphagocytotic cell types (e.g., mesenchymal stem cells, MSCs), weak negative contrast, and decreased MRI signal due to cell proliferation and cellular exocytosis. Herein, we demonstrate that internalization of IO-NP (10 nm) loaded biodegradable poly(lactide-co-glycolide) microparticles (IO/PLGA-MPs, 0.4-3 µm) in MSCs enhances MR parameters such as the r(2) relaxivity (5-fold), residence time inside the cells (3-fold) and R(2) signal (2-fold) compared to IO-NPs alone. Intriguingly, in vitro and in vivo experiments demonstrate that internalization of IO/PLGA-MPs in MSCs does not compromise inherent cell properties such as viability, proliferation, migration and their ability to home to sites of inflammation.

Development of hyaluronic acid-silica composites via in situ precipitation for improved penetration efficiency in fast-dissolving microneedle systems.

Fast-dissolving microneedles (DMNs) hold significant promise for transdermal drug delivery, offering improved patient compliance, biocompatibility, and functional adaptability for various therapeutic purposes. However, the mechanical strength of the biodegradable polymers used in DMNs often proves insufficient for effective penetration into human skin, especially under high humidity conditions. While many composite strategies have been developed to reinforce polymer-based DMNs, simple mixing of the reinforcements with polymers often results in ineffective penetration due to inhomogeneous dispersion of the reinforcements and the formation of undesired micropores. In response to this challenge, this study aimed to enhance the mechanical performance of hyaluronic acid (HA)-based microneedles (MNs), one of the most commonly used DMN systems. We introduced in situ precipitation of silica nanoparticles (Si) into the HA matrix in conjunction with conventional micromolding. The precipitated silica nanoparticles were uniformly distributed, forming an interconnected network within the HA matrix. Experimental results demonstrated that the mechanical properties of the HA-Si composite MNs with up to 20 vol% Si significantly improved, leading to higher penetration efficiency compared to pure HA MNs, while maintaining structural integrity without any critical defects. The composite MNs also showed reduced degradation rates and preserved their drug delivery capabilities and biocompatibility. Thus, the developed HA-Si composite MNs present a promising solution for efficient transdermal drug delivery and address the mechanical limitations inherent in DMN systems. STATEMENT OF SIGNIFICANCE: HA-Si composite dissolving microneedle (DMN) systems were successfully fabricated through in situ precipitation and conventional micromolding processes. The precipitated silica nanoparticles formed an interconnected network within the HA matrix, ranging in size from 25 to 230 nm. The optimal silica content for HA-Si composite MN systems should be up to 20 % by volume to maintain structural integrity and mechanical properties. HA-Si composite MNs with up to 20 % Si showed improved penetration efficiency and reduced degradation rates compared to pure HA MNs, thereby expanding the operational window. The HA-Si composite MNs retained good drug delivery capabilities and biocompatibility.

Wireless, battery-free, multifunctional integrated bioelectronics for respiratory pathogens monitoring and severity evaluation.

The rapid diagnosis of respiratory virus infection through breath and blow remains challenging. Here we develop a wireless, battery-free, multifunctional pathogenic infection diagnosis system (PIDS) for diagnosing SARS-CoV-2 infection and symptom severity by blow and breath within 110 s and 350 s, respectively. The accuracies reach to 100% and 92% for evaluating the infection and symptom severity of 42 participants, respectively. PIDS realizes simultaneous gaseous sample collection, biomarker identification, abnormal physical signs recording and machine learning analysis. We transform PIDS into other miniaturized wearable or portable electronic platforms that may widen the diagnostic modes at home, outdoors and public places. Collectively, we demonstrate a general-purpose technology for rapidly diagnosing respiratory pathogenic infection by breath and blow, alleviating the technical bottleneck of saliva and nasopharyngeal secretions. PIDS may serve as a complementary diagnostic tool for other point-of-care techniques and guide the symptomatic treatment of viral infections.

Transdermal delivery of dextran using conductive microneedles assisted by iontophoresis.

The combination of microneedles (MNs) and iontophoresis (ITP) can enhance the drug penetration in the skin. We previously demonstrated the enhanced delivery of small molecule lidocaine in dentistry by the conductive MNs assisted by ITP. However, the delivery of macromolecules is yet to be explored for this strategy. This study fabricates conductive MNs with polyaniline and hyaluronic acid, which is combined with ITP to deliver dextran macromolecules. This combination improves the penetration of dextran molecules (3-5 kDa, 150 kDa, and 500 kDa) to a depth of around 1536 µm in the agarose gel model. Compared to non-conductive MNs assisted by ITP or conductive MNs alone, conductive MNs assisted by ITP also improves dextran's penetration through the skin, fat, muscle, and cartilage.

Precision cancer sono-immunotherapy using deep-tissue activatable semiconducting polymer immunomodulatory nanoparticles.

Nanomedicine holds promise to enhance cancer immunotherapy; however, its potential to elicit highly specific anti-tumor immunity without compromising immune tolerance has yet to be fully unlocked. This study develops deep-tissue activatable cancer sono-immunotherapy based on the discovery of a semiconducting polymer that generates sonodynamic singlet oxygen (1O2) substantially higher than other sonosensitizers. Conjugation of two immunomodulators via 1O2-cleavable linkers onto this polymer affords semiconducting polymer immunomodulatory nanoparticles (SPINs) whose immunotherapeutic actions are largely inhibited. Under ultrasound irradiation, SPINs generate 1O2 not only to directly debulk tumors and reprogram tumor microenvironment to enhance tumor immunogenicity, but also to remotely release the immunomodulators specifically at tumor site. Such a precision sono-immunotherapy eliminates tumors and prevents relapse in pancreatic mouse tumor model. SPINs show effective antitumor efficacy even in a rabbit tumor model. Moreover, the sonodynamic activation of SPINs confines immunotherapeutic action primarily to tumors, reducing the sign of immune-related adverse events.

Stabilized albumin coatings on engineered xenografts for attenuation of acute immune and inflammatory responses.

Xenogeneic grafts are promising candidates for transplantation therapy due to their easily accessible sources. Nevertheless, the immune and inflammatory responses induced by xenografts need to be addressed for clinical use. A novel and facile method was introduced for the attenuation of immune and inflammatory responses by extending the immune evasion potential of albumin to the tissue engineering field and coating albumin, which could passivate biomaterial surfaces, onto xenografts. Albumin was first modified by dopamine to enhance its adhesion on graft surfaces. Porcine chondrocytes derived living hyaline cartilage graft (LhCG) and decellularized LhCG (dLhCG) were applied as xenograft models implanted in the omentum of rats. Both LhCG which contained porcine chondrocytes as well as secreted ECM and dLhCG which was mainly composed of the porcine source ECM showed alleviated immune and inflammatory responses after being coated with albumin at cell, protein and gene levels, respectively. Significantly less inflammatory cells including neutrophils, macrophages and lymphocytes were recruited according to pathological analysis and immunohistochemistry staining with lower gene expression encoding inflammation-related cytokines including MCP-1, IL-6 and IL-1ß after employing LhCG and dLhCG with albumin passivation coating.

Albumin conjugates and assemblies as versatile bio-functional additives and carriers for biomedical applications.

As the most abundant plasma protein, serum albumin has been extensively studied and employed for therapeutic applications. Despite its direct clinical use for the maintenance of blood homeostasis in various medical conditions, this review exclusively summarizes and discusses albumin-based bio-conjugates and assemblies as versatile bio-functional additives and carriers in biomedical applications. As one of the smallest-sized proteins in the human body, albumin is physiochemically stable and biochemically inert. Moreover, albumin is also endowed with abundant specific binding sites for numerous therapeutic compounds, which also endow it with superior bioactivities. Firstly, due to its small size and binding specificity, albumin alone or its derived assemblies can be utilized as competent drug carriers, which can deliver drugs through the enhanced permeability and retention (EPR) effect or actively target lesion sites through binding with gp60 and secreted protein acidic and rich in cysteine (SPARC) in tumor sites. Furthermore, its biochemical stability and inertness make it a safe and biocompatible coating material for use in biomedical applications. Albumin-based surface modifying additives can be used to functionalize both macro substrates (e.g. surfaces of medical devices or implants) and nanoparticle surfaces (e.g. drug carriers and imaging contrast agents). In this review, we elaborate on the synthesis and applications of albumin-based bio-functional coatings and drug carriers, respectively.

In Situ Generation of Zinc Oxide Nanobushes on Microneedles as Antibacterial Coating.

This paper introduces a facile and scalable method to generate a layer of antibacterial coating on microneedles. The antibacterial coating (i.e., zinc oxide nanobushes) is generated on the surface of gold-coated polystyrene microneedles using the hydrothermal growth method. The antimicrobial property is examined using the agar diffusion test with both gram-positive and gram-negative bacteria.

pH controlled release of chromone from chromone-Fe3O4 nanoparticles.

We report a new strategy for coupling chromone to Fe3O4 nanoparticles. The chromone-Fe3O4 NP conjugate shows a dramatic increase in chromone solubility in cell culture medium from less than 2.5 to 633 microg/ml, leading to the enhanced chromone uptake by HeLa cells. Chromone can be released at low pH and as a result, the chromone-Fe3O4 conjugate is much more efficient in inhibiting the HeLa cell proliferation. Such chromone-Fe3O4 NPs are promising as a powerful multifunctional delivery system for both chromone-based diagnostic and therapeutic applications.

Recent advances in the design of polymeric microneedles for transdermal drug delivery and biosensing.

Microneedles are an efficient and minimally invasive approach to transdermal drug delivery and extraction of skin interstitial fluid. Compared to solid microneedles made of silicon, metals and ceramics, polymeric microneedles have attracted extensive attention due to their excellent biocompatibility, biodegradability and nontoxicity. They are easy to fabricate in large scale and can load drugs in high amounts. More importantly, polymers with different degradation profiles, swelling properties, and responses to biological/physical stimuli can be employed to fabricate polymeric microneedles with different mechanical properties and performance. This review provides a guideline for the selection of polymers and the corresponding fabrication methods for polymeric microneedles while summarizing their recent application in drug delivery and fluid extraction. It should be noted that although polymeric microneedles can achieve efficient transdermal delivery of drugs, their wide applications were limited by their unsatisfactory transdermal therapeutic efficiency. Delivery of nanomedicines that incorporate drugs into functional nanoparticles/capsules can address this problem and thus may be an interesting direction in the future.

Microneedle physical contact as a therapeutic for abnormal scars.

BACKGROUND: Abnormal (keloid and hypertrophic) scars are a significant affliction with no satisfactory single modality therapy to-date. Available options are often ineffective, painful, potentially hazardous, and require healthcare personnel involvement. Herein a self-administered microneedle device based on drug-free physical contact for inhibiting abnormal scars is reported. Its therapeutic activity through microneedle contact eliminates hazards associated with toxic anti-scarring drugs while self-treatment enables administration flexibility. METHODS: The microneedle patch was fabricated with FDA-approved liquid crystalline polymer under good manufacturing practice. It was first tested to ascertain its ability to inhibit (keloid) fibroblast proliferation. Later the microneedle patch was examined on the rabbit ear hypertrophic scar model to explore its potential in inhibiting the generation of abnormal scars post-injury. Finally, the microneedle patch was applied to the caudal region of a hypertrophic scar located on a female patient's dorsum to verify clinical efficacy. RESULTS: On untreated control cultures, barely any non-viable fibroblasts could be seen. After 12-h treatment with the microneedle patch, the non-viable proportion increased to 83.8 ± 11.96%. In rabbit ear hypertrophic scar model, 100% of the control wounds without the presence of patches on rabbit ears generated regions of raised dermis originating from the wound site (3/3), whereas microneedle treatment prevented dermis tissue thickening in 83.33% of the wounds (15/18). In the clinical test, the microneedle patch was well tolerated by the patient. Compared to the untreated region, microneedle treatment decreased the number of infiltrated inflammatory cells, with less disrupted dermis tissue architecture and more flattened appearance. CONCLUSIONS: A self-administered, drug-free microneedle patch appears highly promising in reducing abnormal scarring as observed from in vitro, in vivo and clinical experiments. Larger cohort clinical studies need to be performed to validate its efficacy on abnormal scars.

Near-infrared light-responsive liposomal contrast agent for photoacoustic imaging and drug release applications.

Photoacoustic imaging has become an emerging tool for theranostic applications. Not only does it help in

Layer-by-Layer 3D Constructs of Fibroblasts in Hydrogel for Examining Transdermal Penetration Capability of Nanoparticles.

Nanoparticles are emerging transdermal delivery systems. Their size and surface properties determine their efficacy and efficiency to penetrate through the skin layers. This work utilizes three-dimensional (3D) bioprinting technology to generate a simplified artificial skin model to rapidly screen nanoparticles for their transdermal penetration ability. Specifically, this model is built through layer-by-layer alternate printing of blank collagen hydrogel and fibroblasts. Through controlling valve on-time, the spacing between printing lines could be accurately tuned, which could enable modulation of cell infiltration in the future. To confirm the effectiveness of this platform, a 3D construct with one layer of fibroblasts sandwiched between two layers of collagen hydrogel is used to screen silica nanoparticles with different surface charges for their penetration ability, with positively charged nanoparticles demonstrating deeper penetration, consistent with the observation from an existing study involving living skin tissue.