3-Methylcatechol mediates anti-fecundity effect by inhibiting estrogen-related receptor-induced glycolytic gene expression in Myzus persicae.

Aphids are a major problem in agriculture, horticulture, and forestry by feeding on leaves and stems, causing discoloration, leaf curling, yellowing, and stunted growth. Although urushiol, a phenolic compound containing a catechol structure, is known for its antioxidant and anticancer properties, using small molecules to control aphids via catechol-mediated mechanisms is poorly understood. In this study, we investigated the effects of 3-methylcatechol (3-MC) on Myzus persicae fecundity. Our results showed that treatment with 3-MC significantly reduced the intrinsic transcriptional activity of the aphid estrogen-related receptor (MpERR), which regulates the expression of glycolytic genes. Additionally, 3-MC treatment suppressed the promoter activity of MpERR-induced rate-limiting enzymes in glycolysis, such as phosphofructokinase and pyruvate kinase, by inhibiting MpERR binding. Finally, 3-MC also suppressed MpERR-induced glycolytic gene expression and reduced the number of offspring produced by viviparous female aphids. Overall, our findings suggest that 3-MC has the potential to be used as a new strategy for managing aphid populations by controlling their offspring production.

Enhanced Postsurgical Cancer Treatment Using Methacrylated Glycol Chitosan Hydrogel for Sustained DNA/Doxorubicin Delivery and Immunotherapy.

Background: Cancer recurrence and metastasis are major contributors to treatment failure following tumor resection surgery. We developed a novel implantable drug delivery system utilizing glycol chitosan to address these issues. Glycol chitosan is a natural adjuvant, inducing dendritic cell activation to promote T helper 1 cell immune responses, macrophage activation, and cytokine production. Effective antigen production by dendritic cells initiates T-cell-mediated immune responses, aiding tumor growth control. Methods: In this study, we fabricated multifunctional methacrylated glycol chitosan (MGC) hydrogels with extended release of DNA/doxorubicin (DOX) complex for cancer immunotherapy. We constructed the resection model of breast cancer to verify the anticancer effects of MGC hydrogel with DNA/DOX complex. Results: This study demonstrated the potential of MGC hydrogel with extended release of DNA/DOX complex for local and efficient cancer therapy. The MGC hydrogel was implanted directly into the surgical site after tumor resection, activating tumor-related immune cells both locally and over a prolonged period of time through immune-reactive molecules. Conclusions: The MGC hydrogel effectively suppressed tumor recurrence and metastasis while enhancing immunotherapeutic efficacy and minimizing side effects. This biomaterial-based drug delivery system, combined with cancer immunotherapy, can substantial improve treatment outcomes and patient prognosis.

Polymeric DNase-I nanozymes targeting neutrophil extracellular traps for the treatment of bowel inflammation.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a family of chronic disorders along the gastrointestinal tract. Because of its idiopathic nature, IBD does not have a fundamental cure; current available therapies for IBD are limited to prolonged doses of immunomodulatory agents. While these treatments may reduce inflammation, limited therapeutic efficacy, inconsistency across patients, and adverse side effects from aggressive medications remain as major drawbacks. Recently, excessive production and accumulation of neutrophil extracellular traps (NETs) also known as NETosis have been identified to exacerbate inflammatory responses and induce further tissue damage in IBD. Such discovery invited many researchers to investigate NETs as a potential therapeutic target. DNase-I is a natural agent that can effectively destroy NETs and, therefore, potentially reduce NETs-induced inflammations even without the use of aggressive drugs. However, low stability and rapid clearance of DNase-I remain as major limitations for further therapeutic applications. In this research, polymeric nanozymes were fabricated to increase the delivery and therapeutic efficacy of DNase-I. DNase-I was immobilized on the surface of polymeric nanoparticles to maintain its enzymatic properties while extending its activity in the colon. Delivery of DNase-I using this platform allowed enhanced stability and prolonged activity of DNase-I with minimal toxicity. When administered to animal models of IBD, DNase-I nanozymes successfully alleviated various pathophysiological symptoms of IBD. More importantly, DNase-I nanozyme administration successfully attenuated neutrophil infiltration and NETosis in the colon compared to free DNase-I or mesalamine.

Biofunctional Inorganic Layered Double Hydroxide Nanohybrid Enhances Immunotherapeutic Effect on Atopic Dermatitis Treatment.

Atopic dermatitis (AD) is a widespread, recurrent, and chronic inflammatory skin condition that imposes a major burden on patients. Conventional treatments, such as corticosteroids, are associated with various side effects, underscoring the need for innovative therapeutic approaches. In this study, the possibility of using indole-3-acetic acid-loaded layered double hydroxides (IAA-LDHs) is evaluated as a novel treatment for AD. IAA is an auxin-class plant hormone with antioxidant and anti-inflammatory effects. Following the synthesis of IAA-LDH nanohybrids, their ability to induce M2-like macrophage polarization in macrophages obtained from mouse bone marrow is assessed. The antioxidant activity of IAA-LDH is quantified by assessing the decrease in intracellular reactive oxygen species levels. The anti-inflammatory and anti-atopic characteristics of IAA-LDH are evaluated in a mouse model of AD by examining the cutaneous tissues, immunological organs, and cells. The findings suggest that IAA-LDH has great therapeutic potential as a candidate for AD treatment based on its in vitro and in vivo modulation of AD immunology, enhancement of macrophage polarization, and antioxidant activity. This inorganic drug delivery technology represents a promising new avenue for the development of safe and effective AD treatments.

Anti-Inflammatory Artificial Extracellular Vesicles with Notable Inhibition of Particulate Matter-Induced Skin Inflammation and Barrier Function Impairment.

Particulate matter (PM) exposure disrupts the skin barrier, causing cutaneous inflammation that may eventually contribute to the development of various skin diseases. Herein, we introduce anti-inflammatory artificial extracellular vesicles (AEVs) fabricated through cell extrusion using the biosurfactant PEGylated mannosylerythritol lipid (P-MEL), hereafter named AEVP-MEL. The P-MEL has anti-inflammatory abilities with demonstrated efficacy in inhibiting the secretion of pro-inflammatory mediators. Mechanistically, AEVP-MEL enhanced anti-inflammatory response by inhibiting the mitogen-activated protein kinase (MAPK) pathway and decreasing the release of inflammatory mediators such as reactive oxygen species (ROS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines in human keratinocytes. Moreover, AEVP-MEL promoted increased expression levels of skin barrier proteins (e.g., involucrin, IVL) and water-proteins (e.g., aquaporin 3, AQP3). In vivo studies revealed that repeated PM exposure to intact skin resulted in cutaneous inflammatory responses, including increased skin thickness (hyperkeratosis) and mast cell infiltration. Importantly, our data showed that the AEVP-MEL treatment significantly restored immune homeostasis in the skin affected by PM-induced inflammation and enhanced the intrinsic skin barrier function. This study highlights the potential of the AEVP-MEL in promoting skin health against PM exposure and its promising implications for the prevention and treatment of PM-related skin disorders.

Lipid nanoparticle-based mRNA delivery systems for cancer immunotherapy.

Cancer immunotherapy, which harnesses the power of the immune system, has shown immense promise in the fight against malignancies. Messenger RNA (mRNA) stands as a versatile instrument in this context, with its capacity to encode tumor-associated antigens (TAAs), immune cell receptors, cytokines, and antibodies. Nevertheless, the inherent structural instability of mRNA requires the development of effective delivery systems. Lipid nanoparticles (LNPs) have emerged as significant candidates for mRNA delivery in cancer immunotherapy, providing both protection to the mRNA and enhanced intracellular delivery efficiency. In this review, we offer a comprehensive summary of the recent advancements in LNP-based mRNA delivery systems, with a focus on strategies for optimizing the design and delivery of mRNA-encoded therapeutics in cancer treatment. Furthermore, we delve into the challenges encountered in this field and contemplate future perspectives, aiming to improve the safety and efficacy of LNP-based mRNA cancer immunotherapies.

The ELK3-DRP1 axis determines the chemosensitivity of triple-negative breast cancer cells to CDDP by regulating mitochondrial dynamics.

Triple-negative breast cancer (TNBC) is the most lethal form of breast cancer. TNBC patients have higher rates of metastasis and restricted therapy options. Although chemotherapy is the conventional treatment for TNBC, the frequent occurrence of chemoresistance significantly lowers the efficacy of treatment. Here, we demonstrated that ELK3, an oncogenic transcriptional repressor that is highly expressed in TNBC, determined the chemosensitivity of two representative TNBC cell lines (MDA-MB231 and Hs578T) to cisplatin (CDDP) by regulating mitochondrial dynamics. We observed that the knockdown of ELK3 in MDA-MB231 and Hs578T rendered these cell lines more susceptible to the effects of CDDP. We further demonstrated that the chemosensitivity of TNBC cells was caused by the CDDP-mediated acceleration of mitochondrial fission, excessive mitochondrial reactive oxygen species production, and subsequent DNA damage. In addition, we identified DNM1L, a gene encoding the dynamin-related protein 1 (a major regulator of mitochondrial fission), as a direct downstream target of ELK3. Based on these results, we propose that the suppression of ELK3 expression could be used as a potential therapeutic strategy for overcoming the chemoresistance or inducing the chemosensitivity of TNBC.

Systemic Delivery of a STING Agonist-Loaded Positively Charged Liposome Selectively Targets Tumor Immune Microenvironment and Suppresses Tumor Angiogenesis.

Although stimulator of interferon genes (STING) agonists has shown great promise in preclinical studies, the clinical development of STING agonist therapy is challenged by its limited systemic delivery. Here, positively charged fusogenic liposomes loaded with a STING agonist (PoSTING) are designed for systemic delivery and to preferentially target the tumor microenvironment. When PoSTING is administered intravenously, it selectively targets not only tumor cells but also immune and tumor endothelial cells (ECs). In particular, delivery of STING agonists to tumor ECs normalizes abnormal tumor vasculatures, induces intratumoral STING activation, and elicits robust anti-tumor T cell immunity within the tumor microenvironment. Therefore, PoSTING can be used as a systemic delivery platform to overcome the limitations of using STING agonists in clinical trials.

Multifunctional porous microspheres encapsulating oncolytic bacterial spores and their potential for cancer immunotherapy.

Clostridium novyi-NT (C. novyi-NT) is an anaerobic bacterium that can be used for targeted cancer therapy because it germinates selectively in the hypoxic regions of tumor tissues. However, systemic administration of C. novyi-NT spores cannot effectively treat tumors because of the limited intratumoral delivery of active spores. In this study, we demonstrated that multifunctional porous microspheres (MPMs) containing C. novyi-NT spores have the potential for image-guided local tumor therapy. The MPMs can be repositioned under an external magnetic field, enabling precise tumor targeting and retention. Polylactic acid-based MPMs were prepared using the oil-in-water emulsion technique and then coated with a cationic polyethyleneimine polymer prior to loading with negatively charged C. novyi-NT spores. The C. novyi-NT spores delivered by MPMs were released and germinated in a simulated tumor microenvironment, effectively secreting proteins cytotoxic to tumor cells. In addition, the germinated C. novyi-NT induced immunogenic death of the tumor cells and M1 polarization of macrophages. These results indicate that MPMs encapsulated with C. novyi-NT spores have great potential for image-guided cancer immunotherapy.

Uniform Gold Nanostructure Formation via Weakly Adsorbed Gold Films and Thermal Annealing for Reliable Localized Surface Plasmon Resonance-Based Detection of DNase-I.

Deoxyribonuclease-I (DNase-I), a representative endonuclease, is an important biomarker for the diagnosis of infectious diseases and cancer progression. However, enzymatic activity decreases rapidly ex vivo, which highlights the need for precise on-site detection of DNase-I. Here, a localized surface plasmon resonance (LSPR) biosensor that enables the simple and rapid detection of DNase-I is reported. Moreover, a novel technique named electrochemical deposition and mild thermal annealing (EDMIT) is applied to overcome signal variations. By taking advantage of the low adhesion of gold clusters on indium tin oxide substrates, both the uniformity and sphericity of gold nanoparticles are increased under mild thermal annealing conditions via coalescence and Ostwald ripening. This ultimately results in an approximately 15-fold decrease in LSPR signal variations. The linear range of the fabricated sensor is 20-1000 ng mL-1 with a limit of detection (LOD) of 127.25 pg mL-1 , as demonstrated by spectral absorbance analyses. The fabricated LSPR sensor stably measured DNase-I concentrations from samples collected from both an inflammatory bowel disease (IBD) mouse model, as well as human patients with severe COVID-19 symptoms. Therefore, the proposed LSPR sensor fabricated via the EDMIT method can be used for early diagnosis of other infectious diseases.

Nanoparticle-Based Chimeric Antigen Receptor Therapy for Cancer Immunotherapy.

Adoptive cell therapy with chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) has emerged as an innovative immunotherapy for hematological cancer treatment. However, the limited effect on solid tumors, complex processes, and excessive manufacturing costs remain as limitations of CAR-T therapy. Nanotechnology provides an alternative to the conventional CAR-T therapy. Owing to their unique physicochemical properties, nanoparticles can not only serve as a delivery platform for drugs but also target specific cells. Nanoparticle-based CAR therapy can be applied not only to T cells but also to CAR-natural killer and CAR-macrophage, compensating for some of their limitations. This review focuses on the introduction of nanoparticle-based advanced CAR immune cell therapy and future perspectives on immune cell reprogramming.

Reprogramming the tumor microenvironment with biotechnology.

The tumor microenvironment (TME) is a unique environment that is developed by the tumor and controlled by tumor-induced interactions with host cells during tumor progression. The TME includes immune cells, which can be classified into two types: tumor- antagonizing and tumor-promoting immune cells. Increasing the tumor treatment responses is associated with the tumor immune microenvironment. Targeting the TME has become a popular topic in research, which includes polarizing macrophage phenotype 2 into macrophage phenotype 1 using Toll-like receptor agonists with cytokines, anti-CD47, and anti-SIPRα. Moreover, inhibiting regulatory T cells through blockades and depletion restricts immunosuppressive cells in the TME. Reprogramming T cell infiltration and T cell exhaustion improves tumor infiltrating lymphocytes, such as CD8+ or CD4+ T cells. Targeting metabolic pathways, including glucose, lipid, and amino acid metabolisms, can suppress tumor growth by restricting the absorption of nutrients and adenosine triphosphate energy into tumor cells. In conclusion, these TME reprogramming strategies exhibit more effective responses using combination treatments, biomaterials, and nanoparticles. This review highlights how biomaterials and immunotherapy can reprogram TME and improve the immune activity.

Liposome-mediated small RNA delivery to convert the macrophage polarity: A novel therapeutic approach to treat inflammatory uterine disease.

Macrophages are present in all tissues for maintaining tissue homeostasis, and macrophage polarization plays a vital role in alleviating inflammation. Therefore, specific delivery of polarization modulators to macrophages in situ is critical for treating inflammatory diseases. We demonstrate that a size-controlled miRNA-encapsulated macrophage-targeting liposomes (miR/MT-Lip) specifically targets macrophages to promote M1-to-M2 polarization conversion, alleviating inflammation without cytotoxicity. miR/MT-Lip, approximately 1.2 µm, showed excellent internalization through phagocytosis and/or macropinocytosis in macrophages. miR-10a/MT-Lip, but not scramble miR-Fluorescein amidite (FAM)/MT-Lip as control, effectively converted the polarization of lipopolysaccharide (LPS)-induced M1 macrophages to M2 in vitro. When miR-10a/MT-Lip was intravenously delivered to mice insulted with LPS for inflammation, the proportion of M2 macrophages was significantly increased without disturbing the population of other immune cells. Furthermore, scramble miR-FAM/MT-Lip was mainly detected in macrophages, but not other immune cells. When our miR/MT-Lip was administered to mice with Asherman's syndrome that suffer from infertility because of sterile uterine inflammation, macrophage-specific targeting of miR-10a/MT-Lip facilitated M1-to-M2 conversion for angiogenesis in the impaired uterus, resulting in restoration of healthy uterine conditions. The results indicate that our MT-Lip encapsulating small RNAs has excellent potential to treat various inflammatory disorders by fine-tuning macrophage polarization in vivo without any side effects.

Biofunctional Layered Double Hydroxide Nanohybrids for Cancer Therapy.

Layered double hydroxides (LDHs) with two-dimensional nanostructure are inorganic materials that have attractive advantages such as biocompatibility, facile preparation, and high drug loading capacity for therapeutic bioapplications. Since the intercalation chemistry of DNA molecules into the LDH materials were reported, various LDH nanohybrids have been developed for biomedical drug delivery system. For these reasons, LDHs hybridized with numerous therapeutic agents have a significant role in cancer imaging and therapy with targeting functions. In this review, we summarized the recent advances in the preparation of LDH nanohybrids for cancer therapeutic strategies including gene therapy, chemotherapy, immunotherapy, and combination therapy.

Corrigendum: Editorial: Advanced nanotechnology for reactive oxygen species-mediated therapies.

[This corrects the article DOI: 10.3389/fmolb.2022.1000113.].

Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma.

Patients with high-risk non-metastatic renal cell carcinoma (RCC) are at risk of metastatic relapse following nephrectomy. Cabozantinib (CZ), a potent multitarget tyrosine kinase inhibitor, interferes with angiogenesis and immunosuppression associated with surgery-induced metastasis. Here, we explored the therapeutic potential of CZ-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CZ-PLGA-NPs) as an adjuvant strategy for targeting post-nephrectomy metastasis. A clinically relevant subline recapitulating post-nephrectomy lung metastasis of high-risk human RCC, namely Renca-SRLu5-Luc, was established through in vivo serial selection of luciferase-expressing murine RCC Renca-Luc cells. CZ was encapsulated into PLGA-NPs via the conventional single emulsion technique. The multifaceted preclinical antimetastatic efficacy of CZ-PLGA-NPs was assessed in Renca-SRLu5-Luc cells. CZ-PLGA-NPs with a smooth surface displayed desirable physicochemical properties, good CZ encapsulation efficiency, as well as controlled and sustained CZ release. CZ-PLGA-NPs exhibited remarkable dose-dependent toxicity against Renca-SRLu5-Luc cells by inducing G2/M cell cycle arrest and apoptosis. CZ-PLGA-NPs attenuated in vitro colony formation, migration, and invasion by abrogating AKT and ERK1/2 activation. An intravenous injection of CZ-PLGA-NPs markedly reduced lung metastatic burden and prolonged lifespan with favorable safety in the Renca-SRLu5-Luc experimental lung metastasis model. The novel CZ-PLGA-NPs system with multifaceted antimetastatic effects and alleviating off-target toxicity potential is a promising adjunctive agent for patients with surgically resected high-risk RCC.

Image-guided in situ cancer vaccination with combination of multi-functional nano-adjuvant and an irreversible electroporation technique.

Cancer immunotherapy is a next-generation treatment strategy; however, its side effects limit its clinical translation. Here, a novel combination of a multi-functional nano-adjuvant (M-NA) prepared with an iron oxide/gold core and a cationic polymer shell via multilayer synthesis with CpG oligodeoxynucleotide (CpG-ODN) electrostatically complexed on its surface, and irreversible electroporation (IRE) technique was developed for effective image-guided in situ cancer vaccination. The M-NA can be retained long-term in the dense tumoral extracellular matrix after intratumoral injection and internalized by antigen-presenting cells (APCs). The IRE can induce immunogenic cell death. Indeed, in a mouse tumor model, the M-NA showed longer tumor retention time than free CpG-ODN. Compared with other treatments, the combined treatment significantly inhibited tumor growth with 100% survival rate for ∼60 days. The therapy induced the activation of cytotoxic lymphocytes and the maturation of APCs in vivo. This treatment could be effective in image-guided local cancer immunotherapy.

Nuclear receptor estrogen-related receptor modulates antimicrobial peptide expression for host innate immunity in Tribolium castaneum.

Antimicrobial peptides (AMPs) are core components of innate immunity to protect insects against microbial infections. Nuclear receptors (NRs) are ligand-dependent transcription factors that can regulate the expression of genes critical for insect development including molting and metamorphosis. However, the role of NRs in host innate immune response to microbial infection remains poorly understood in Tribolium castaneum (T. castaneum). Here, we show that estrogen-related receptor (ERR), an insect ortholog of the mammalian ERR family of NRs, is a novel transcriptional regulator of AMP genes for innate immune response of T. castaneum. Tribolium ERR (TcERR) expression was induced by immune deficiency (IMD)-Relish signaling in response to infection by Escherichia coli (E. coli), a Gram-negative bacterium, as demonstrated in TcIMD-deficient beetles. Interestingly, genome-wide transcriptome analysis of TcERR-deficient old larvae using RNA-sequencing analysis showed that TcERR expression was positively correlated with gene transcription levels of AMPs including attacins, defensins, and coleoptericin. Moreover, chromatin immunoprecipitation analysis revealed that TcERR could directly bind to ERR-response elements on promoters of genes encoding defensin3 and coleoptericin, critical for innate immune response of T. castaneum. Finally, TcERR-deficient old larvae infected with E. coli displayed enhanced bacterial load and significantly less host survival. These findings suggest that TcERR can coordinate transcriptional regulation of AMPs and host innate immune response to bacterial infection.

Reactive Oxygen Species Responsive Cleavable Hierarchical Metallic Supra-Nanostructure.

A reactive oxygen species (ROS) responsive cleavable hierarchical metallic supra-nanostructure (HMSN) is reported. HMSN structured with thin branches composed of primary gold (Au) nanocrystals and silver (Ag) nano-linkers is synthesized by a one-pot aqueous synthesis with a selected ratio of Au/Ag/cholate. ROS responsive degradability of HMSN is tested in the presence of endogenous and exogeneous ROS. Significant ROS-responsive structural deformation of HMSN is observed in the ROS exposure with hydrogen peroxide (H2 O2 ) solution. The ROS responsiveness of HMSN is significantly comparable with negligible structural changes of conventional spherical gold nanoparticles. The demonstrated ROS responsive degradation of HMSN is further confirmed in various in vitro ROS conditions of each cellular endogenous ROS and exogeneous ROS generated by photodynamic therapy (PDT) or X-ray radiation. Then, in vivo ROS responsive degradability of HMSN is further evaluated with intratumoral injection of HMSN and exogeneous ROS generation via PDT in a mouse tumor model. Additional in vivo biodistribution and toxicity of intravenously administrated HMSN at 30-day post-injection are investigated for potential in vivo applications. The observed ROS responsive degradability of HMSN will provide a promising option for a type of ROS responsive-multifunctional nanocarriers in cancer treatment and various biomedical applications.