Targeted pH-Activated Peptide-Based Nanomaterials for Combined Photodynamic Therapy with Immunotherapy.

Photodynamic therapy (PDT) has demonstrated efficacy in eliminating local tumors, yet its effectiveness against metastasis is constrained. While immunotherapy has exhibited promise in a clinical context, its capacity to elicit significant systemic antitumor responses across diverse cancers is often limited by the insufficient activation of the host immune system. Consequently, the combination of PDT and immunotherapy has garnered considerable attention. In this study, we developed pH-responsive porphyrin-peptide nanosheets with tumor-targeting capabilities (PRGD) that were loaded with the IDO inhibitor NLG919 for a dual application involving PDT and immunotherapy (PRGD/NLG919). In vitro experiments revealed the heightened cellular uptake of PRGD/NLG919 nanosheets in tumor cells overexpressing αvß3 integrins. The pH-responsive PRGD/NLG919 nanosheets demonstrated remarkable singlet oxygen generation and photocytotoxicity in HeLa cells in an acidic tumor microenvironment. When treating HeLa cells with PRGD/NLG919 nanosheets followed by laser irradiation, a more robust adaptive immune response occurred, leading to a substantial proliferation of CD3+CD8+ T cells and CD3+CD4+ T cells compared to control groups. Our pH-responsive targeted PRGD/NLG919 nanosheets therefore represent a promising nanosystem for combination therapy, offering effective PDT and an enhanced host immune response.

Analytical models of electron leakage currents in gallium nitride-based laser diodes and light-emitting diodes.

The electrical-to-optical power conversion efficiencies of the light-emitting devices based on gallium nitride (GaN) are seriously limited by electron leakage currents due to the relatively low mobility and activation ratio of holes. However, there have been few theoretical models on the behavior of the leakage current with an increasing total current. We develop an Ohmic-law-like method to describe the transport behaviors of the systems with electron and hole currents simultaneously. Based on reasonable assumptions, the ratio of the leakage current to the total current is related to the differential resistances of the devices. Through the method, we develop analytical models of the leakage currents in GaN-based laser diodes (LDs) and light-emitting diodes (LEDs). The ratios of the leakage currents with total currents in LDs and LEDs are shown to increase, which explains the sublinear behaviors of the luminescence-current (LI) curves of the devices. The theory agrees well with the numerical simulation and experimental results in larger current ranges in comparison to the traditional ABC model. The above analytical model can be used to fast evaluate the leakage currents in GaN-based LDs and LEDs.

Room-temperature polariton lasing in GaN microrods with large Rabi splitting.

Room-temperature polariton lasing is achieved in GaN microrods grown by metal-organic vapor phase epitaxy. We demonstrate a large Rabi splitting (Ω = 2g0) up to 162 meV, exceeding the results from both the state-of-the-art nitride-based planar microcavities and previously reported GaN microrods. An ultra-low threshold of 1.8 kW/cm2 is observed by power-dependent photoluminescence spectra, with the linewidth down to 1.31 meV and the blue shift up to 17.8 meV. This large Rabi splitting distinguishes our coherent light emission from a conventional photon lasing, which strongly supports the preparation of coherent light sources in integrated optical circuits and the study of exciting phenomena in macroscopic quantum states.

Bioinspired Two-Dimensional Structure with Asymmetric Wettability Barriers for Unidirectional and Long-Distance Gas Bubble Delivery Underwater.

Gas bubble manipulations in liquid have long been a concern because of their vital roles in various gas-related fields. To deal with the weakness in long-distance gas transportation of previous works, we took inspiration from the ridgelike structure on Nepenthes pitcher's peristome and successfully prepared a two-dimensional superaerophilic surface decorated with asymmetric aerophobic barriers capable of unidirectional and long-distance gas bubble delivery. For the first time, this process was investigated by in situ bubble-releasing experiments recorded by a high-speed camera and finite element modeling, which demonstrates a kinetic process regulated by the anisotropic motion resistance arising from the patterns. Furthermore, the Nepenthes alata-inspired two-dimensional surface (NATS) was integrated into a water electrolysis system for H2 directional transportation and efficient collection. As a result, the NATS design was proved to be a potential solution for facile manipulation of gas bubbles and provides a simple, adaptive, and reliable strategy for long-range gas transport underwater.

Two-round quasi-whispering gallery mode exciton polaritons with large Rabi splitting in a GaN microrod.

We investigate the exciton polaritons and their corresponding optical modes in a hexagonal GaN microrod at room temperature. The dispersion curves are measured by the angle-resolved micro-photoluminescence spectrometer, and two types of exciton polaritons are identified with the help of the finite-difference time-domain simulation. By changing the pump position, the photon part of the exciton polaritons is found to switch between the quasi-whispering gallery modes and the two-round quasi-whispering gallery modes. The exciton polaritons formed by the latter are observed and distinguished for the first time, with a giant Rabi splitting as large as 2Ω = 230.3 meV.

Surfactant-free amorphous solid dispersion with high dissolution for bioavailability enhancement of hydrophobic drugs: a case of quercetin.

At present, saccharides as hydrophilic matrixes, have been gradually used in amorphous solid dispersions (ASD) for dispersing poorly water-soluble drugs without surfactants. In this study, an amorphous chitosan oligosaccharide (COS) was applied as a water-soluble matrix to form surfactant-free ASD via the ball milling to vitrify quercetin (QUE) and enhance the dissolution and bioavailability. Solid-state characterization (DSC, XRPD, FTIR, SEM and PLM) and physical stability assessments verified that the prepared ASDs showed excellent physical stability with complete amorphization due to potential interactions between QUE and COS. In vitro sink dissolution tests suggested all QUE-COS ASDs (w:w, 1:1, 1:2 and 1:4) significantly enhanced the dissolution rate of QUE. Meanwhile, in vitro non-sink dissolution exhibited that the maximum supersaturated concentration ranged from 112.62 to 138.00 µg/mL for all QUE-COS ASDs, which was much higher than that of pure QUE. Besides, the supersaturation of QUE-COS ASD kept for at least 24 h. In rat pharmacokinetics, the oral bioavailability of QUE-COS ASDs showed 1.64 ∼ 2.25 times increase compared to the pure QUE (p < .01). Hence, the present study confirms the amorphous COS could be applied as a promising hydrophilic matrix in QUE-COS ASDs for enhancing dissolution performance and bioavailability of QUE.

Covalently Assembled Dipeptide Nanoparticles with Adjustable Fluorescence Emission for Multicolor Bioimaging.

Peptide self-assembly, inspired by the naturally occurring fabrication principle, remains the most attractive in constructing fluorescent nanoagents towards bioimaging. However, the noncovalent interactions that drive peptide self-assembly are usually susceptible to the complex physiological environment; thus leading to disassembly and dysfunction of fluorescent nanoagents. Herein, a covalently crosslinked assembly strategy for fabrication of stable peptide-based nanoparticles with adjustable emission is introduced. In the process of cationic diphenylalanine peptide (H-Phe-Phe-NH2 ⋅HCl) self-assembly, glutaraldehyde is used as a crosslinker and the resulting product of the Schiff base reaction can be fluorescent. More importantly, the emission wavelength can be readily tuned by controlling the covalent reaction time. It has been demonstrated that the nanoparticles are stable, even after intracellular uptake, and can be used for sustainable multicolor fluorescent imaging. The strategy with integrating peptide self-assembly and covalent crosslinking could be promising for the design and engineering of functional fluorescent nanoparticles with robust physiological stability and adjustable emission towards improved bioimaging applications.

Spatiotemporally Coupled Photoactivity of Phthalocyanine-Peptide Conjugate Self-Assemblies for Adaptive Tumor Theranostics.

Spatiotemporally coupled tumor phototheranostic platforms offer a flexible and precise system that takes the biological interaction between tumors and photoactive agents into consideration for optimizing treatment, which is highly consistent with precision medicine. However, the fabrication of monocomponent-based photoactive agents applicable to multifold imaging techniques and multiple therapies in a facile way remains challenging. In this study, we developed simple phthalocyanine-peptide (PF) conjugate-based monocomponent nanoparticles with spatiotemporally coupled photoactivity for adaptive tumor theranostics. The self-assembled PF nanoparticles possess well-defined spherical nanostructures and excellent colloidal stability along with supramolecular photothermal effects. Importantly, the PF nanoparticles showed switchable photoactivity triggered by their interactions with the cell membrane, which enables an adaptive transformation from photothermal therapy (PTT) and photoacoustic imaging (PAI) to photodynamic therapy (PDT) and corresponding fluorescence imaging (FI). Theranostic modalities are integrated in a spatiotemporally coupled manner, providing a facile, biocompatible and effective route for localized tumor phototherapy. This study offers a flexible and versatile strategy to integrate multiple theranostic modalities into a single component so that it can realize its full potential and thereby amplify its therapeutic efficacy, creating promising opportunities for the design of theranostics and further highlighting their clinical prospects to the diagnosis and treatment of cancers.

Smart Peptide-Based Supramolecular Photodynamic Metallo-Nanodrugs Designed by Multicomponent Coordination Self-Assembly.

Supramolecular photosensitizer nanodrugs that combine the flexibility of supramolecular self-assembly and the advantage of spatiotemporal, controlled drug delivery are promising for dedicated, precise, noninvasive tumor therapy. However, integrating robust blood circulation and targeted burst release in a single photosensitizer nanodrug platform that can simultaneously improve the therapeutic performance and reduce side effects is challenging. Herein, we demonstrate a multicomponent coordination self-assembly strategy that is versatile and potent for the development of photodynamic nanodrugs. Inspired by the multicomponent self-organization of polypeptides, pigments, and metal ions in metalloproteins, smart metallo-nanodrugs are constructed based on the combination and cooperation of multiple coordination, hydrophobic, and electrostatic noncovalent interactions among short peptides, photosensitizers, and metal ions. The resulting metallo-nanodrugs have uniform sizes, well-defined nanosphere structures, and high loading capacities. Most importantly, multicomponent assembled nanodrugs have robust colloidal stability and ultrasensitive responses to pH and redox stimuli. These properties prolong blood circulation, increase tumor accumulation, and enhance the photodynamic tumor therapeutic efficacy. This study offers a new strategy to harness robust, smart metallo-nanodrugs with integrated flexibility and multifunction to enhance tumor-specific delivery and therapeutic effects, highlighting opportunities to develop next-generation, smart photosensitizing nanomedicines.

Effectiveness of an app-based intervention for unintentional injury among caregivers of preschoolers: protocol for a cluster randomized controlled trial.

BACKGROUND: Each year, over 15,000 preschoolers die from unintentional injuries in China. Many interventions proven to work in other nations have not been implemented nationwide in China. The rapid popularity of smartphones offers an opportunity to overcome this limitation and disseminate evidence-based interventions to the large population of China. This study aims to assess the effectiveness of an app-based intervention for caregivers of preschoolers to prevent unintentional injury among young Chinese children. METHOD: A single-blinded, 6-month, parallel-group cluster randomized controlled trial with 1:1 allocation ratio will be conducted in Changsha, China. In total, 2626 caregivers of preschoolers ages 3-6 years old who own a smartphone will be recruited from 20 preschools. Clusters will be randomized at the preschool level and allocated to either the control group (routine education plus app-based parenting education excluding unintentional injury prevention) or the intervention group (routine education plus app-based parenting education including unintentional injury prevention). The app-based injury prevention program was developed based on the Theory of Planned Behavior, the Haddon Matrix, the Mobile Learning framework, and a needs assessment. Data collection will be conducted at baseline, 3-month, and 6-month follow-up via app-based survey plus printed questionnaire survey. The primary outcome measure is unintentional injury incidence among preschoolers in the past 3 months. Secondary outcome measures include economic losses due to unintentional injury in the past 3 months, the Incremental Cost-Effectiveness Ratios (ICERs), and parent's attitudes and behaviors concerning supervision to prevent preschooler unintentional injury in the past week. An intention-to-treat approach will be used to evaluate outcome measures. Chi-square tests will examine differences for outcome measures between groups at each time point and generalized estimation equations (GEE) will test the overall effectiveness of the app-based intervention. Missing outcome data will be imputed using the Expectation Maximization algorithm (EM). DISCUSSION: This trial will examine evidence concerning the effectiveness of an innovative app-based intervention for caregivers of Chinese preschoolers. If effective, the app-based intervention could offer an effective population-based intervention option to cost-effectively promote unintentional injury prevention in countries and regions where injury control is under-supported. TRIAL REGISTRATION: ChiCTR-IOR-17010438 . Registered 15 January 2017.

Amino Acid Coordination Driven Self-Assembly for Enhancing both the Biological Stability and Tumor Accumulation of Curcumin.

Clinical translation of curcumin has been highly obstructed by the rapid degradation and poor tissue absorption of this agent. Herein, we report on the generation of supramolecular curcumin nanoagents through amino acid coordination driven self-assembly to simultaneously increase the biological stability and tumor accumulation of curcumin. The biological stability of curcumin was significantly improved both through coordination and through molecular stacking. The sizes of these nanoagents can be readily manipulated to facilitate tumor accumulation. These favorable therapeutic features, together with high drug-loading capacities and responses to pH and redox stimuli, substantially enhanced the antitumor activity of curcumin without discernible side effects. Hence, supramolecular curcumin nanoagents may hold promise in moving forward the clinical application of curcumin as an effective anticancer drug.

Charge-Induced Secondary Structure Transformation of Amyloid-Derived Dipeptide Assemblies from ß-Sheet to α-Helix.

Secondary structures such as α-helix and ß-sheet are the major structural motifs within the three-dimensional geometry of proteins. Therefore, structure transitions from ß-sheet to α-helix not only can serve as an effective strategy for the therapy of neurological diseases through the inhibition of ß-sheet aggregation but also extend the application of α-helix fibrils in biomedicine. Herein, we present a charge-induced secondary structure transition of amyloid-derived dipeptide assemblies from ß-sheet to α-helix. We unravel that the electrostatic (charge) repulsion between the C-terminal charges of the dipeptide molecules are responsible for the conversion of the secondary structure. This finding provides a new perspective to understanding the secondary structure formation and transformation in the supramolecular organization and life activity.

Biological Photothermal Nanodots Based on Self-Assembly of Peptide-Porphyrin Conjugates for Antitumor Therapy.

Photothermal agents can harvest light energy and convert it into heat, offering a targeted and remote-controlled way to destroy carcinomatous cells and tissues. Inspired by the biological organization of polypeptides and porphyrins in living systems, here we have developed a supramolecular strategy to fabricate photothermal nanodots through peptide-modulated self-assembly of photoactive porphyrins. The self-assembling nature of porphyrins induces the formation of J-aggregates as substructures of the nanodots, and thus enables the fabrication of nanodots with totally inhibited fluorescence emission and singlet oxygen production, leading to a high light-to-heat conversion efficiency of the nanodots. The peptide moieties not only provide aqueous stability for the nanodots through hydrophilic interactions, but also provide a spatial barrier between porphyrin groups to inhibit the further growth of nanodots through the strong π-stacking interactions. Thermographic imaging reveals that the conversion of light to heat based on the nanodots is efficient in vitro and in vivo, enabling the nanodots to be applied for photothermal acoustic imaging and antitumor therapy. Antitumor therapy results show that these nanodots are highly biocompatible photothermal agents for tumor ablation, demonstrating the feasibility of using bioinspired nanostructures of self-assembling biomaterials for biomedical photoactive applications.

Self-Assembled Injectable Peptide Hydrogels Capable of Triggering Antitumor Immune Response.

Self-assembled peptide hydrogels are particularly appealing for drug delivery, tissue engineering, and antitumor therapy due to various advantageous features including excellent biocompatibility and biodegradability, defined molecular and higher organized structures, and easy availability. However, the poor mechanical and rheological properties of assembled peptide hydrogels cause difficulties in injection, thus limiting further applications. Herein, injectable peptide-based hydrogels with tunable mechanical and rheological properties were obtained by combination with a positively charged poly peptide (poly-l-lysine, PLL). Electrostatic coupling between PLL and a self-assembling dipeptide (Fmoc-FF) provides a smart switch to enable the fibrous hydrogels to be shear-thinning and self-healing, thus leading to the formation of supramolecular hydrogels with rheological properties suitable for injection. The latter can be flexibly adjusted by merely varying the concentration or the molecular weight of the polypeptide to satisfy a variety of requirements in biological applications. The hydrogels, consisting of helical nanofibers stabilized with disulfide bonds, are prepared and further injected for antitumor therapy. The results demonstrate that the helical fibrous hydrogel, without the addition of antigens, immune regulatory factors, and adjuvants, can activate T cell response and efficiently suppress tumor growth. Therefore, injectable hydrogels self-assembled by a combination of small peptides and biomacromolecules present a great potential for biomedical applications, especially for development of a new type of immuno-responsive materials toward antitumor therapy.

Multiscale simulations for understanding the evolution and mechanism of hierarchical peptide self-assembly.

Hierarchical self-assembly, abundant in biological systems, has been explored as an effective bottom-up method to fabricate highly ordered functional superstructures from elemental building units. Biomolecules, especially short peptides consisting of several amino acids, are a type of elegant building blocks due to their advantages of structural, mechanical, and functional diversity as well as high biocompatibility and biodegradability. The hierarchical self-assembly of peptides is a spontaneous process spanning multiple time and length scales under certain thermodynamics and kinetics conditions. Therefore, understanding the mechanisms of dynamic processes is crucial to directing the construction of complicated biomimetic systems with multiple functionalities. Multiscale molecular simulations that combine and systematically link several hierarchies can provide insights into the evolution and dynamics of hierarchical self-assembly from the molecular level to the mesoscale. Herein, we provided an overview of the simulation hierarchies in the general field of peptide self-assembly modeling. In particular, we highlighted multiscale simulations for unraveling the mechanisms underlying the dynamic self-assembly process with an emphasis on weak intermolecular interactions in the process stages and the energies of different molecular alignments as well as the role of thermodynamic and kinetic factors at the microscopic level.

Co-Assembly of Heparin and Polypeptide Hybrid Nanoparticles for Biomimetic Delivery and Anti-Thrombus Therapy.

Biomimetic delivery carriers using polypeptide/heparin hybrid nanoparticles that are adsorbed onto red blood cells for extended blood circulation time have been developed. This might open up an avenue to promote the innovations and advances of biomimetic, stimuli-responsive drug delivery, especially for the site-specific treatment of intravascular diseases such as thrombosis.

Two-photon nanoprobes based on bioorganic nanoarchitectonics with a photo-oxidation enhanced emission mechanism.

Two-photon absorption (TPA) fluorescence imaging holds great promise in diagnostics and biomedicine owing to its unparalleled spatiotemporal resolution. However, the adaptability and applicability of currently available TPA probes, which act as a critical element for determining the imaging contrast effect, is severely challenged by limited photo-luminescence in vivo. This is particularly a result of uncontrollable aggregation that causes fluorescence quenching, and inevitable photo-oxidation in harsh physiological milieu, which normally leads to bleaching of the dye. Herein, we describe the remarkably enhanced TPA fluorescence imaging capacity of self-assembling near-infrared (NIR) cyanine dye-based nanoprobes (NPs), which can be explained by a photo-oxidation enhanced emission mechanism. Singlet oxygen generated during photo-oxidation enables chromophore dimerization to form TPA intermediates responsible for enhanced TPA fluorescence emission. The resulting NPs possess uniform size distribution, excellent stability, more favorable TPA cross-section and anti-bleaching ability than a popular TPA probe rhodamine B (RhB). These properties of cyanine dye-based TPA NPs promote their applications in visualizing blood circulation and tumoral accumulation in real-time, even to cellular imaging in vivo. The photo-oxidation enhanced emission mechanism observed in these near-infrared cyanine dye-based nanoaggregates opens an avenue for design and development of more advanced TPA fluorescence probes.

Proper use of light environments for mitigating the effects of COVID-19 and other prospective public health emergency lockdowns on sleep quality and fatigue in adolescents.

Coronavirus disease 2019 (COVID-19) remains a public health emergency of international concern, and some countries still implement strict regional lockdowns. Further, the upcoming 2023 Asian Games and World University Games will implement a closed-loop management system. Quarantine can harm mental and physical health, to which adolescents are more vulnerable compared with adults. Previous studies indicated that light can affect our psychology and physiology, and adolescents were exposed to the artificial light environment in the evening during the lockdown. Thus, this study aimed to establish and assess appropriate residential light environments to mitigate the effects of lockdowns on sleep quality and fatigue in adolescents. The participants were 66 adolescents (12.15 ± 2.45 years of age) in a closed-loop management environment, who participated in a 28-day (7-day baseline, 21-day light intervention) randomized controlled trial of a light-emitting diode (LED) light intervention. The adolescents were exposed to different correlated color temperature (CCT) LED light environments (2000 K or 8000 K) for 1 h each evening. The results for self-reported daily sleep quality indicated that the low CCT LED light environment significantly improved sleep quality (p < 0.05), and the blood test results for serum urea and hemoglobin indicated that this environment also significantly reduced fatigue (p < 0.05) and moderately increased performance, compared to the high CCT LED light environment. These findings can serve as a springboard for further research that aims to develop interventions to reduce the effects of public health emergency lockdowns on mental and physical health in adolescents, and provide a reference for participants in the upcoming Asian Games and World University Games.

Synthesis and biological evaluation of novel amprenavir-based P1-substituted bi-aryl derivatives as ultra-potent HIV-1 protease inhibitors.

A series of P1-substituted biaryl amprenavir derivatives was designed and synthesized. These compounds were evaluated for enzyme inhibition and antiviral activity in vitro. Several compounds showed highly efficient antiviral activity with EC(50) values down to 0.10nM, which are more potent than marketed HIV-1 protease inhibitors. Docking study indicated that 12c has similar binding mode to amprenavir with full occupancy in P1.

Peptide-based supramolecular assembly drugs toward cancer theranostics.

INTRODUCTION: Peptide-based supramolecular self-assembly has been demonstrated to be a flexible approach for the fabrication of programmable de novo nanodrugs by employing synergistic or reciprocal intermolecular non-covalent interactions. This class of nanomaterials holds significant promise for clinical translation, especially as cancer theranostics. AREAS COVERED: In this review, we describe the concept of cancer theranostic drug assembly by employing non-covalent interactions. That is, molecular drugs are formulated into nanoscale and even microscale architectures by peptide-modulated self-assembly. A series of peptide-based supramolecular assembly drugs are discussed, with an emphasis on the relation between structural feature and theranostic performance. EXPERT OPINION: Molecular design, manipulation of non-covalent interactions, and elucidation of structure-function relationships not only facilitate the implementation of supramolecular self-assembly principles in drug development, but also provide a new means for advancing anticancer nanostructured drugs toward clinical application.