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RNA interference (RNAi)-based biopesticides offer an attractive avenue for pest control. Previous studies revealed high RNAi sensitivity in Holotrichia parallela larvae, showcasing its potential for grub control. In this study, we aimed to develop an environmentally friendly RNAi method for H. parallela larvae. The double-stranded RNA (dsRNA) of the V-ATPase-a gene ( HpVAA ) was loaded onto layered double hydroxide (LDH). The dsRNA/LDH nanocomplex exhibited increased environmental stability, and we investigated the absorption rate and permeability of dsRNA-nanoparticle complexes and explored the RNAi controlling effect. Silencing the HpVAA gene was found to darken the epidermis of H. parallela larvae, with growth cessation or death or mortality, disrupting the epidermis and midgut structure. Quantitative reverse transcription-polymerase chain reaction and confocal microscopy confirmed the effective absorption of the dsRNA/LDH nanocomplex by peanut plants, with distribution in roots, stems, and leaves. Nanomaterial-mediated RNAi silenced the target genes, leading to the death of pests. Therefore, these findings indicate the successful application of the nanomaterial-mediated RNAi system for underground pests, thus establishing a theoretical foundation for developing a green, safe, and efficient pest control strategy.

Therapeutic proteins are playing increasingly important roles in treating numerous types of diseases. However, oral administration of proteins, especially large ones (e.g., antibodies), remains a great challenge due to their difficulties in penetrating intestinal barriers. Herein, fluorocarbon-modified chitosan (FCS) is developed for efficient oral delivery of different therapeutic proteins, in particular large ones such as immune checkpoint blockade antibodies. In our design, therapeutic proteins are mixed with FCS to form nanoparticles, lyophilized with appropriate excipients, and then filled into enteric capsules for oral administration. It has been found that FCS could promote transmucosal delivery of its cargo protein via inducing transitory rearrangement of tight junction associated proteins between intestinal epithelial cells and subsequently release free proteins into blood circulation. It is shown that at a 5-fold dose oral delivery of anti-programmed cell death protein-1 (αPD1) or its combination with anti-cytotoxic T-lymphocyte antigen 4 (αCTLA4) using this method could achieve comparable antitumor therapeutic responses to that achieved by intravenous injection of corresponding free antibodies in various types of tumor models and, more excitingly, result in significantly reduced immune-related adverse events. Our work successfully demonstrates the enhanced oral delivery of antibody drugs to achieve systemic therapeutic responses and may revolutionize the future clinical usage of protein therapeutics.

Immune checkpoint blockade (ICB) treatment for the clinical therapy of numerous malignancies has attracted widespread attention in recent years. Despite being a promising treatment option, developing complementary strategies to enhance the proportion of patients benefiting from ICB therapy remains a formidable challenge because of the complexity of the tumor microenvironment. Ibrutinib (IBR), a covalent inhibitor of Bruton's tyrosine kinase (BTK), has been approved as a clinical therapy for numerous B-cell malignancies. IBR also irreversibly inhibits interleukin-2 inducible T cell kinase (ITK), an essential enzyme in Th2-polarized T cells that participates in tumor immunosuppression. Ablation of ITK by IBR can elicit Th1-dominant antitumor immune responses and potentially enhance the efficacy of ICB therapy in solid tumors. However, its poor solubility and rapid clearance in vivo restrict T cell targetability and tumor accumulation by IBR. A sialic acid derivative-modified nanocomplex (SA-GA-OCT@PC) has been reported to improve the efficacy of IBR-mediated combination immunotherapy in solid tumors. In vitro and in vivo experiments showed that SA-GA-OCT@PC effectively accumulated in tumor-infiltrating T cells mediated by Siglec-E and induced Th1-dominant antitumor immune responses. SA-GA-OCT@PC-mediated combination therapy with PD-L1 blockade agents dramatically suppressed tumor growth and inhibited tumor relapse in B16F10 melanoma mouse models. Overall, the combination of the SA-modified nanocomplex platform and PD-L1 blockade offers a treatment opportunity for IBR in solid tumors, providing novel insights for tumor immunotherapy.

Inspired by the natural phenomenon of phenolic-protein interactions, we translate this "naturally evolved interaction" to a "phenolic acid derivative based albumin bound" technology, through the synthesis of phenolic acid derivatives comprising a therapeutic cargo linked to a phenolic motif. Phenolic acid derivatives can bind to albumin and form nanocomplexes after microfluidic mixing. This strategy has been successfully applied to different types of anticancer drugs, including taxanes, anthraquinones, etoposides, and terpenoids. Paclitaxel was selected as a model drug for an in-depth study. Three novel paclitaxel-phenolic acid conjugates have been synthesized. Molecular dynamics simulations provide insights into the self-assembled mechanisms of phenolic-protein nanocomplexes. The nanocomplexes show improved pharmacokinetics, elevated tolerability, decreased neurotoxicity, and enhanced anticancer efficacies in multiple murine xenograft models of breast cancer, in comparison with two clinically approved formulations, Taxol (polyoxyethylated castor oil-formulated paclitaxel) and Abraxane (nab-paclitaxel). Such a robust system provides a broadly applicable platform for the development of albumin-based nanomedicines and has great potential for clinical translation.

Immunotherapeutic efficacy of tumors based on immune checkpoint blockade (ICB) therapy is frequently limited by an immunosuppressive tumor microenvironment and cross-reactivity with normal tissues. Herein, we develop reactive oxygen species (ROS)-responsive nanocomplexes with the function of ROS production for delivery and triggered release of anti-mouse programmed death ligand 1 antibody (αPDL1) and glucose oxidase (GOx). GOx and αPDL1 were complexed with oligomerized (-)-epigallocatechin-3- O -gallate (OEGCG), which was followed by chelation with Fe 3+ and coverage of the ROS-responsive block copolymer, POEGMA- b -PTKDOPA, consisting of poly(oligo(ethylene glycol)methacrylate) (POEGMA) and the block with thioketal bond-linked dopamine moieties (PTKDOPA) as the side chains. After intravenous injection, the nanocomplexes show prolonged circulation in the bloodstream with a half-life of 8.72 h and efficient tumor accumulation. At the tumor sites, GOx inside the nanocomplexes can produce H 2 O 2 via oxidation of glucose for Fenton reaction to generate hydroxyl radicals (•OH) which further trigger the release of the protein cargos through ROS-responsive cleavage of thioketal bonds. The released GOx improves the production efficiency of •OH to kill cancer cells for release of tumor-associated antigens via chemodynamic therapy (CDT). The enhanced immunogenic cell death (ICD) can activate the immunosuppressive tumor microenvironment and improve the immunotherapy effect of the released αPDL1, which significantly suppresses primary and metastatic tumors. Thus, the nanocomplexes with Fenton reaction-triggered protein release show great potentials to improve the immunotherapeutic efficacy of ICB via combination with CDT.

In this study, we chemically modified a phytoglycogen structure to introduce negative surface charge via carboxymethylation (CMPG) and then prepared CMPG-based ternary nanocomplex particles through electrostatic interactions with sodium caseinate (core) and chemical cross-linking with pectin (shell). The chemical cross-linking process by glutaradehyde was systematically optimized under various temperatures and durations. The cross-linked ternary nanocomplex was comprehensively characterized, and our results showed that it had a size of 86 nm with a spherical shape, smooth surface, homogeneous distribution, and negative surface charge. The chemical cross-linking process significantly improved colloidal stability of the nanocomplex under simulated gastrointestinal fluids with digestive enzymes. The as-prepared nanocomplex exhibited exceptional capability to encapsulate phloretin, a natural dihydrochalcone, as a model lipophilic bioactive compound. The nanocomplex not only showed a slow and sustained kinetic release of phloretin under simulated gastrointestinal fluids but also dramatically enhanced its antioxidant activity under an aqueous environment compared to pure phloretin dissolved in ethanol. Findings from this work revealed the promising features of the as-prepared ternary nanocomplex as a potential oral delivery system for lipophilic bioactive compounds.

Salmon calcitonin (sCT) is a potent calcium-regulating peptide hormone and widely applied for the treatment of some bone diseases clinically. However, the therapeutic usefulness of sCT is hindered by the frequent injection required, owing to its short plasma half-life and therapeutic need for a high dose. Oral delivery is a popular modality of administration for patients because of its convenience to self-administration and high patient compliance, while orally administered sCT remains a great challenge currently due to the existence of multiple barriers in the gastrointestinal (GI) tract. Here, we introduced an orally targeted delivery system to increase the transport of sCT across the intestine through both the paracellular permeation route and the bile acid pathway. In this system, sCT-based glycol chitosan-taurocholic acid conjugate (GC-T)/dextran sulfate (DS) ternary nanocomplexes (NC-T) were produced by a flash nanocomplexation (FNC) process in a kinetically controlled mode. The optimized NC-T exhibited well-controlled properties with a uniform and sub-60 nm hydrodynamic diameter, high batch-to-batch reproducibility, good physical or chemical stability, as well as sustained drug release behaviors. The studies revealed that NC-T could effectively improve the intestinal uptake and permeability, owing to its surface functionalization with the taurocholic acid ligand. In the rat model, orally administered NC-T showed an obvious hypocalcemia effect and a relative oral bioavailability of 10.9%. An in vivo assay also demonstrated that NC-T induced no observable side effect after long-term oral administration. As a result, the orally targeted nanocomplex might be a promising candidate for improving the oral transport of therapeutic peptides.

Noninvasive real-time biosensors to measure glucose levels in the body fluids have been widely investigated for continuous glucose monitoring of diabetic patients. However, they suffered from low sensitivity and reproducibility due to the instability of nanomaterials used for glucose biosensors. Here, we developed a hyaluronate-gold nanoparticle/glucose oxidase (HA-AuNP/GOx) complex and an ultralow-power application-specific integrated circuit chip for noninvasive and robust wireless patch-type glucose sensors. The HA-AuNP/GOx complex was prepared by the facile conjugation of thiolated HA to AuNPs and the following physical binding of GOx. The wireless glucose sensor exhibited slow water evaporation (0.11 μL/min), fast response (5 s), high sensitivity (12.37 μA·dL/mg·cm 2 ) and selectivity, a low detection limit (0.5 mg/dL), and highly stable enzymatic activity (∼14 days). We successfully demonstrated the strong correlation between glucose concentrations measured by a commercially available blood glucometer and the wireless patch-type glucose sensor. Taken together, we could confirm the feasibility of the wireless patch-type robust glucose sensor for noninvasive and continuous diabetic diagnosis.

Zeolitic imidazolate frameworks (ZIFs), a group of metal-organic frameworks (MOFs), hold promise as building blocks in electromagnetic (EM) wave absorbing/shielding materials and devices. In this contribution, we proposed a facile strategy to synthesize three-dimensional ZIF-67-based hierarchical heterostructures through coordinated reaction of a preceramic component, poly(dimethylsilylene)diacetylene (PDSDA) with ZIF-67, followed by carbonizing the PDSDA-wrapped ZIF at high temperature. The introduction of PDSDA leads to controllable generation of a surface network containing branched carbon nanotubes and regional distributed graphitic carbons, in addition to the nanostructures with a well-defined size and porous surface made by cobalt nanoparticles. The surface structures can be tailored through variations in pyrolysis temperatures, therefore enabling a simple and robust route to facilitate a suitable structural surface. The heterostructure of the ZIF nanocomplex allows the existence of dielectric loss and magnetic loss, therefore yielding a significant improvement on EM wave absorption with a minimum reflection coefficient (RC min ) of -50.9 dB at 17.0 GHz at a thickness of 1.9 mm and an effective absorption bandwidth (EAB) covering the full Ku-band (12.0-18.0 GHz).

The mortality of ovarian cancer stably ranks first in gynecological malignancies due to the lack of specific symptoms and diagnostic methods at an early stage. For most patients, the cancer cells had metastasized before they were diagnosed. As a result, 90% of them died of multidrug resistance (MDR) to chemotherapeutics. In our study, RNAi technology was introduced and applied to overcome this big problem. LAH4-L1, an amphipathic cationic polypeptide, was reported to have high transfection efficiency and was first selected by us to deliver siMDR1 for overcoming ovarian cancer cells MDR. In this research, LAH4-L1-siRNA nanocomplexes (LSCs) delivery system was designed via electrostatic interactions. The nanocomplexes could realize 87.3% MDR1 gene silence and 85% P-gp down-regulation on SKOV-3 cells. What's more, with the combination of chemotherapeutics, SKOV-3 cells growth inhibition can reach to 82.9%. We have also found that there was about 50% reduction on cells migration when MDR1 gene was down-regulated. Besides what have been mentioned above, physicochemical characteristics, cytotoxicity, pH responsivity, cells cycle, cellular uptake, and endosomal escape abilities were also studied in this research. In conclusion, lower cytotoxicity, higher down-regulation of targeted gene, and great cell inhibition, when combined with chemotherapeutics, all show the great potential of LSCs for the reversal of multidrug resistance on SKOV-3 cells in the future.

Protein-based drug delivery carrier has been one of the most employed modalities in biopharmaceuticals. In this study, we have compared avidin and its two analogues, neutravidin and streptavidin, as nanocarriers for the delivery of biotin-labeled siRNA with the help of biotinylated cholesterol (targeting ligand) and protamine (condensing agent). These proteins have similar binding affinity to biotin but substantial difference in their physical and chemical characteristics. Here, we have shown how these characteristics affect the size, cellular uptake, and activity of the avidin-based siRNA nanocomplex. In contrast to avidin and streptavidin nanocomplexes, neutravidin-based nanocomplex shows very low endosome entrapment and high cytoplasmic localization at extended times. High amount of the siRNA released in the cytoplasm by neutravidin-based nanocomplex at extended times (24 h) results in extensive and sustained PCBP2 gene silencing activity in HSC-T6 rat hepatic stellate cells. Neutravidin-based nanocomplex shows significantly low exocytosis in comparison to the streptavidin-based nanocomplex. Avidin-, neutravidin-, and streptavidin-based nanocomplexes are similar in size and had no significant cytotoxicity in transfected HSC-T6 cells or inflammatory cytokine induction in a whole blood assay. Compared to free siRNA, the neutravidin-based siRNA nanocomplex exhibits higher accumulation at 2 h in the liver of the rats with CCl 4 -induced liver fibrosis. Neutravidin has therefore been shown to be the most promising avidin analogue for the delivery of siRNA.

Photoacoustic tomography (PAT) is a newly emerging noninvasive imaging modality that could be further enhanced using near-infrared (NIR)-absorbing materials as contrast agents. To date, the most extensively studied photoacoustic imaging agents are inorganic nanomaterials because organic materials with NIR-absorption capabilities are limited. In this study, a NIR-absorbing nanocomplex composed of a squaraine dye (SQ) and albumin was prepared based on the aggregation-induced NIR absorption of SQ. Through aggregation, the absorption spectrum of SQ was widened from the visible-light region to the NIR region, which facilitated photoacoustic signal generation in the tissue-transparent NIR optical window (700-900 nm). Blood analysis and histology measurements revealed that the nanocomplex can be used for PAT applications in vivo without obvious toxicity to living mice.