Triboelectric Nanogenerators-Based Therapeutic Electrical Stimulation on Skin: from Fundamentals to Advanced Applications.

Discovery of the amazing and vital therapeutic roles of electrical stimulation (ES) on skin has sparked tremendous efforts to investigate ES suppliers. Among them, triboelectric nanogenerators (TENGs), as a self-sustainable bioelectronic system, can generate self-powered and biocompatible ES for achieving superior therapeutic effects on skin applications. Here, a brief review of the application of TENGs-based ES on skin is presented, with specific discussions of the fundamentals of TENGs-based ES and its feasibility to be applied for adjusting physiological and pathological processes of skin. Then, a comprehensive and in-depth depiction of emerging representative skin applications of TENGs-based ES is categorized and reviewed, with particular descriptions about its therapeutic effects on achieving antibacterial therapy, promoting wound healing, and facilitating transdermal drug delivery. Finally, the challenges and perspectives for further advancing TENGs-based ES toward a more powerful and versatile therapeutic strategy are discussed, particularly regarding opportunities in fundamental multidisciplinary research and biomedical applications.

Efficient epidermal delivery of antibiotics by self-assembled lecithin/chitosan nanoparticles for enhanced therapy on epidermal bacterial infections.

The treatment for epidermal bacterial infections has become a primary healthy concern, producing a significant therapeutic challenge. Here we present a facile strategy to fabricate lecithin/chitosan nanoparticles (LCNPs) for efficient epidermal drug delivery over epidermal bacterial infections. The central rotatable composite design method was used for the optimization of the preparation, and that the optimal size (212.63 ± 1.95 nm) was obtained via analysis of variance (ANOVA). The prepared CIP-LCNPs show an average diameter of 325.9 ± 7.4 nm and a zeta potential of 26.6 ± 1.2 mV. Antibiotics can be well encapsulated in LCNPs and its release kinetics is studied with cumulative release of 93.81 ± 2.05 % for 48 h. The hemolytic activity, cytotoxicity, and skin irritation are further investigated. The zones of inhibition are 2.16 ± 0.04 cm and 2.92 ± 0.03 cm for Escherichia coli and Staphylococcus aureus, respectively. Moreover, in vitro permeation studies demonstrate that LCNPs can increase the accumulation of antibiotics in the epidermis with retention ratio 2-3 fold higher than commercial formulations. The in vivo result over epidermal-infected wound demonstrates the superior therapeutic effects of LCNPs. The developed LCNPs represent an important advance in fabricating therapeutic materials for enhanced therapy over epidermal bacterial infections.

Iodinated cyanine dye-based nanosystem for synergistic phototherapy and hypoxia-activated bioreductive therapy.

Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species (ROS) to kill cancer cells. However, the effectiveness of PDT is greatly reduced due to local hypoxia. Hypoxic activated chemotherapy combined with PDT is expected to be a novel strategy to enhance anti-cancer therapy. Herein, a novel liposome (LCT) incorporated with photosensitizer (PS) and bioreductive prodrugs was developed for PDT-activated chemotherapy. In the design, CyI, an iodinated cyanine dye, which could simultaneously generate enhanced ROS and heat than other commonly used cyanine dyes, was loaded into the lipid bilayer; while tirapazamine (TPZ), a hypoxia-activated prodrug was encapsulated in the hydrophilic nucleus. Upon appropriate near-infrared (NIR) irradiation, CyI could simultaneously produce ROS and heat for synergistic PDT and photothermal therapy (PTT), as well as provide fluorescence signals for precise real-time imaging. Meanwhile, the continuous consumption of oxygen would result in a hypoxia microenvironment, further activating TPZ free radicals for chemotherapy, which could induce DNA double-strand breakage and chromosome aberration. Moreover, the prepared LCT could stimulate acute immune response through PDT activation, leading to synergistic PDT/PTT/chemo/immunotherapy to kill cancer cells and reduce tumor metastasis. Both in vitro and in vivo results demonstrated improved anticancer efficacy of LCT compared with traditional PDT or chemotherapy. It is expected that these iodinated cyanine dyes-based liposomes will provide a powerful and versatile theranostic strategy for tumor target phototherapy and PDT-induced chemotherapy.

Tumor Microenvironment-triggered Nanosystems as dual-relief Tumor Hypoxia Immunomodulators for enhanced Phototherapy.

Photodynamic therapy (PDT) is a promising strategy in cancer treatment that utilizes photosensitizers (PSs) to produce reactive oxygen species (ROS) and eliminate cancer cells under specific wavelength light irradiation. However, special tumor environments, such as those with overexpression of glutathione (GSH), which will consume PDT-mediated ROS, as well as hypoxia in the tumor microenvironment (TME) could lead to ineffective treatment. Moreover, PDT is highly light-dependent and therefore can be hindered in deep tumor cells where light cannot easily penetrate. To solve these problems, we designed oxygen-dual-generating nanosystems MnO2@Chitosan-CyI (MCC) for enhanced phototherapy. Methods: The TME-sensitive nanosystems MCC were easily prepared through the self-assembly of iodinated indocyanine green (ICG) derivative CyI and chitosan, after which the MnO2 nanoparticles were formed as a shell by electrostatic interaction and Mn-N coordinate bonding. Results: When subjected to NIR irradiation, MCC offered enhanced ROS production and heat generation. Furthermore, once endocytosed, MnO2 could not only decrease the level of GSH but also serve as a highly efficient in situ oxygen generator. Meanwhile, heat generation-induced temperature increase accelerated in vivo blood flow, which effectively relieved the environmental tumor hypoxia. Furthermore, enhanced PDT triggered an acute immune response, leading to NIR-guided, synergistic PDT/photothermal/immunotherapy capable of eliminating tumors and reducing tumor metastasis. Conclusion: The proposed novel nanosystems represent an important advance in altering TME for improved clinical PDT efficacy, as well as their potential as effective theranostic agents in cancer treatment.

Targeted nanocarriers based on iodinated-cyanine dyes as immunomodulators for synergistic phototherapy.

Photodynamic therapy (PDT), as one of the most powerful photo-therapeutic strategies for cancer treatment with minimum invasiveness, can effectively damage local tumor cells and significantly induce systemic antitumor immunity. However, current nanotechnology-assisted PDT-immunomodulators have either poor penetration for deep tumors or low singlet oxygen generation. Herein, we construct a novel theranostic nanocarrier (HA-PEG-CyI, HPC) by inducing the self-assembly of PEGylated CyI and attaching the ligand HA to its surface. The prepared HPC can be used as an ideal PDT-immunomodulator for synergistic cancer therapy. CyI is an iodinated-cyanine dye with enhanced singlet oxygen generation ability as well as excellent photo-to-photothermal and near-infrared fluorescence imaging properties. Under 808 nm laser irradiation, the prepared HPC can generate both reactive oxygen species (ROS) and elevate temperature which can subsequently result in apoptosis and necrosis at tumor sites. Moreover, the HPC-induced cell death can generate a series of acute inflammatory reactions, leading to systemic immunity induction and secondary death of tumor cells, which further results in reducing tumor recurrence. In vitro and in vivo results show that HPC can enhance the tumor targeting efficacy, generate ROS efficiently and exhibit a high temperature response under NIR irradiation, which working together can activate immune responses for synergistic phototherapy on tumor cells. Accordingly, the proposed multi-functional HPC nanocarriers represent an important advance in PDT and can be used as a superior cancer treatment strategy with great promise for clinical applications.