Plant-derived artificial miRNA effectively reduced the proliferation of aphid (Aphidoidea) through spray-induced gene silencing.

BACKGROUND: Aphids (Hemiptera: Aphididae) are notorious sap-sucking insects that rampantly threaten agricultural production worldwide. Current management against aphids in the field heavily relies on chemical pesticides, which makes economical and eco-friendly methods urgently needed. Spray-induced gene silencing (SIGS) offers a powerful and precise approach to pest management. However, the high costs and instability of double-stranded RNA (dsRNA) regulators applied for downstream RNA interference (RNAi) still limit this strategy. It remains uncertain if RNAi regulators applied in SIGS could extend to small RNA (sRNA), especially miRNA. RESULTS: We chose two sRNA sequences, miR-9b and miR-VgR, whose corresponding targets ABCG4 and VgR are both essential for aphid growth and development. The efficacy of these sequences was initially verified by chemically synthetic single-stranded RNA (syn-ssRNA). Through spray treatment, we observed a significantly decreased survival number and increased abnormality rate of green peach aphids fed on the host under laboratory conditions. Based on our previous study, we generated transgenic plants expressing artificial miR-9b (amiR-9b) and miR-VgR (amiR-VgR). Remarkably, plant-derived amiRNA exerted potent and long-lasting inhibitory efficacy with merely one percent concentration of chemical synthetics. Notably, the simultaneous application of amiR-9b and amiR-VgR exhibited superior inhibitory efficacy. CONCLUSION: We explored the potential use of sRNA-based biopesticide through SIGS while investigating the dosage requirements. To optimize this strategy, the utilization of plant-derived amiRNA was proposed. The results suggested that attributed to stability and durability, deploying amiRNA in pest management is a potential and promising solution for the field application. © 2024 Society of Chemical Industry.

CPPs-modified chitosan as permeability-enhancing chemotherapeutic combined with gene therapy nanosystem by thermosensitive hydrogel for the treatment of osteosarcoma.

BACKGROUND: Chemotherapy resistance of osteosarcoma (OS) is still the crux of poor clinical curative effect.E3 ubiquitin-protein ligase Rad18 (Rad18) contributed to doxorubicin resistance in OS, which ultimately mediated DNA damage tolerance and led to a poor prognosis and chemotherapy response in patients. METHODS: In this study, doxorubicin was loaded in the process of Fe2+ and siRad18 forming nanoparticles(FSD) through coordination, chitosan modified with cell penetrating peptide (H6R6) was synthesized and coated on the surface of the NPs(FSD-CHR). FSD-CHR was then dispersed in thermosensitive hydrogel(PPP) for peritumoral injection of osteosarcoma in situ. Subsequently, the physicochemical properties and molecular biological characteristics of the drug delivery system were characterized. Finally, an osteosarcoma model was established to study the anti-tumor effects of multifunctional nanoparticles and the immunotherapy effect combined with αPD-L1. RESULTS: FSD-CHR has enhanced tumor tissue permeability, siRad18 can significantly reduce Dox-mediated DNA damage tolerance and enhance anti-tumor effects, and iron-based NPs show enhanced ROS upregulation. FSD-CHR@PPP showed significant inhibition of osteosarcoma growth in vivo and a reduced incidence of lung metastasis. In addition, siRad18 was unexpectedly found to enhance Dox-mediated immunogenic cell death (ICD).FSD-CHR@PPP combined with PD-L1 blocking significantly enhanced anti-tumor effects due to decreased PD-L1 enrichment. CONCLUSION: Hydrogel encapsulation of permeable nanoparticles provides an effective strategy for doxorubicin-resistant OS, showing that gene therapy blocking DNA damage tolerance can enhance treatment response to chemotherapy and appears to enhance the effect of ICD inducers to activate the immune system.

Targeted Extracellular Protein Degradation by Dendronized DNA Chimeras.

Extracellular soluble proteins are key agents in the development of various diseases. However, strategies to remove therapeutically relevant extracellular targets are still scarce. Here, we establish dendronized DNA chimera (DENTAC) as an efficient approach for targeted degradation of the extracellular protein of interest (ePOI). DENTAC consists of a DNA dendron against cell-surface scavenger receptors (SRs), a protein ligand, and a connecting linker, which harnesses SRs as a lysosome-trafficking receptor to mediate the lysosomal degradation of the ePOI. We interrogate and optimize structure-activity relationships of DENTAC. Using neutravidin as a model ePOI, we show that both branch number and DNA length in the DNA dendron are important determinants for efficient lysosomal delivery and degradation of the protein. We demonstrate three branches and 10 nucleotide-length polythymidine as the optimal DNA dendron components to construct DENTAC. We further exemplify the anticancer application of DENTAC by targeting matrix metalloproteinase-9 (MMP-9), where we find linker property as another factor important for DENTAC performance. We reveal that MMP-9-targeting DENTAC effectively restrain cancer cell proliferation, migration, and invasion. This study thus provides a potent strategy to delete extracellular proteins that are commonly difficult to target.

Self-Assembled Nano-PROTAC Enables Near-Infrared Photodynamic Proteolysis for Cancer Therapy.

Confining the protein degradation activity of proteolysis-targeting chimera (PROTAC) to cancer lesions ensures precision treatment. However, it still remains challenging to precisely control PROTAC function in tumor regions in vivo. We herein describe a near-infrared (NIR) photoactivatable nano-PROTAC (NAP) for remote-controllable proteolysis in tumor-bearing mice. NAP is formed by molecular self-assembly from an amphiphilic conjugate of PROTAC linked with an NIR photosensitizer through a singlet oxygen (1O2)-cleavable linker. The activity of PROTAC is initially silenced but can be remotely switched on upon NIR photoirradiation to generate 1O2 by the photosensitizer. We demonstrated that NAP enabled tumor-specific degradation of bromodomain-containing protein 4 (BRD4) in an NIR light-instructed manner. This in combination with photodynamic therapy (PDT) elicited an effective suppression of tumor growth. This work thus presents a novel approach for spatiotemporal control over targeted protein degradation by PROTAC.

Dendronized DNA Chimeras Harness Scavenger Receptors To Degrade Cell Membrane Proteins.

Bispecific chimeras bridging cell membrane proteins with lysosome-trafficking receptors (LTRs) provide an effective therapeutic approach through lysosomal degradation of disease-relevant targets. Here, we report a novel dendronized DNA chimera (DENTAC) strategy that uses a dendritic DNA to engage cell surface scavenger receptors (SRs) as LTR. Using bioorthogonal strain-promoted alkyne-azide cycloaddition to conjugate the dendritic DNA with protein binder, the resulting DENTAC is able to traffic the protein target into the lysosome for elimination. We demonstrated the utility of DENTAC by degrading oncogenic membrane nucleolin (NCL) and epidermal growth factor receptor (EGFR). The anti-cancer application of NCL-targeting DENTAC was validated in a mouse xenograft model of lung cancer. This work thus presents a new avenue for rapid development of potent degraders against membrane proteins, with also broad research and therapeutic prospects.

Influence of Evidence-Based Nursing on Psychological Status, Neurological Function, and Life Quality of Patients with Acute Poststroke Depression.

Objective: This research sets out to elucidate the influence of evidence-based nursing (EBN) on psychological status (PSY), neurological function, and quality of life (QoL) of patients with acute poststroke depression (PSD). Methods: One hundred and fifty stroke patients who received treatment in the Characteristic Medical Center of PLA Rocket Force between December 2019 and December 2021 were enrolled, including 100 cases (Group A) treated with comprehensive EBN and 50 patients (Group B) with routine nursing. Anxiety and depression (Self-Rating Anxiety Scale [SAS] and Self-Rating Depression Scale [SDS] scores), neurological function (National Institutes of Health Stroke Scale [NIHSS] and Scandinavian Stroke Scale [SSS] scores), QoL (Generic Quality Of Life Inventory-74 [GQOLI-74] score), and complication rate of both groups were evaluated, as well as total effective rate and nursing satisfaction. Results: Group A outperformed Group B with lower scores of NIHSS, SSS, SAS, and SDS and higher GOOLI-74 scores. Besides, lower complication rate and higher total effective rate and nursing satisfaction were determined in Group A. Conclusions: EBN can better improve the PSY of patients with acute PSD, restore their neurological function, and effectively improve their QoL.

Molecular platforms based on biocompatible photoreactions for photomodulation of biological targets.

Photoirradiation provides a convenient and biocompatible approach for spatiotemporal modulation of biological systems with photoresponsive components. The construction of molecular platforms with a photoresponse to be integrated into biomolecules for photomodulation has been of great research interest in optochemical biology. In this review, we summarize typical molecular platforms that are integratable with biomolecules for photomodulation purposes. We categorize these molecular platforms according to their excitation light source, namely ultraviolet (UV), visible (Vis) or near-infrared (NIR) light. The protype chemistry of these molecular platforms is introduced along with an overview of their most recent applications for spatiotemporal regulation of biomolecular function in living cells or mice models. Challenges and the outlook are also presented. We hope this review paper will contribute to further progress in the development of molecular platforms and their biomedical use.

Photo-controllable bioorthogonal chemistry for spatiotemporal control of bio-targets in living systems.

The establishment of bioorthogonal chemistry is one of the most significant advances in chemical biology using exogenous chemistry to perturb and study biological processes. Photo-modulation of biological systems has realized temporal and spatial control on biomacromolecules in living systems. The combination of photo-modulation and bioorthogonal chemistry is therefore emerging as a new direction to develop new chemical biological tools with spatiotemporal resolution. This minireview will focus on recent development of bioorthogonal chemistry subject to spatiotemporal control through photo-irradiation. Different strategies to realize photo-control on bioorthogonal bond-forming reactions and biological applications of photo-controllable bioorthogonal reactions will be summarized to give a perspective on how the innovations on photo-chemistry can contribute to the development of optochemical biology. Future trends to develop more optochemical tools based on novel photochemistry will also be discussed to envision the development of chemistry-oriented optochemical biology.