Micro- and nano-plastics (MPs and NPs) released from plastics in the environment can enter the food chain and target the human intestine. However, knowledge about the effects of these particles on the human intestine is still limited due to the lack of relevant human intestinal models to validate data obtained from animal studies or tissue models employing cancer cells. In this study, human intestinal organoids were used to develop epithelia to mimic the cell complexity and functions of native tissue. Microfold cells (M cells) were induced to distinguish their role when exposure to MPs and NPs. During the exposure, the M cells acted as sensors, capturers and transporters of larger sized particles. The epithelial cells internalized the particles in a size-, concentration-, and time-dependent manner. Importantly, high concentrations of particles significantly triggered the secretion of a panel of inflammatory cytokines linked to human inflammatory bowel disease (IBD).

Immunotherapy efficacy as monotherapy is negligible for glioblastoma (GBM). We hypothesized that combining therapeutic vaccination using a plasmid encoding an epitope derived from GBM-associated antigen (pTOP) with local delivery of immunogenic chemotherapy using mitoxantrone-loaded PEGylated PLGA-based nanoparticles (NP-MTX) would improve the survival of GBM-bearing mice by stimulating an antitumor immune response. We first proved that MTX retained its ability to induce cytotoxicity and immunogenic cell death of GBM cells after encapsulation. Intratumoral delivery of MTX or NP-MTX increased the frequency of IFN-γ-secreting CD8 T cells. NP-MTX mixed with free MTX in combination with pTOP DNA vaccine increased the median survival of GL261-bearing mice and increased M1-like macrophages in the brain. The addition of CpG to this combination abolished the survival benefit but led to increased M1 to M2 macrophage ratio and IFN-γ-secreting CD4 T cell frequency. These results highlight the benefits of combination strategies to potentiate immunotherapy and improve GBM outcome.

Porous polymer microspheres are employed in biotherapeutics, tissue engineering, and regenerative medicine. Porosity dictates cargo carriage and release that are aligned with the polymer physicochemical properties. These include material tuning, biodegradation, and cargo encapsulation. How uniformity of pore size affects therapeutic delivery remains an area of active investigation. Herein, we characterize six branched aliphatic hydrocarbon-based porogen(s) produced to create pores in single and multilayered microspheres. The porogens are composed of biocompatible polycaprolactone, poly(lactic-co-glycolic acid), and polylactic acid polymers within porous multilayered microspheres. These serve as controlled effective drug and vaccine delivery platforms.

The second near-infrared (NIR-II) fluorescence imaging has attracted continuous attention due to its excellent penetration depth and high spatial resolution. Compared with other fluorophores, NIR-II fluorophores, especially NIR-II organic small molecule fluorophores, are favored because of their controllable structure and good biocompatibility. In this study, we designed and synthesized an S-D-A-D-S type small molecule FEA. However, a new molecule was accidentally obtained in the process of synthesis, which was proved to be a double receptor (A-A) type small molecule, namely S-D-A-A-D-S type organic small molecule FEAA. Compared with FEA molecules, FEAA exhibits superior fluorescence performance and can effectively prevent fluorescence quenching. The fluorescence emission of its nanoparticles (NPs) reaches 1109 nm, extends to about 1400 nm, and has a Stokes shift of up to 472 nm. Subsequently, we realized fluorescence/photoacoustic dual-mode imaging (FI/PAI) of nude mouse liver, and finally effectively ablated 4T1 tumor by photothermal therapy (PTT). In general, FEAA NPs exhibit good fluorescence, photoacoustic, and photothermal effects, and are an excellent multifunctional NIR-II organic small molecule fluorophore. As far as we know, there are few reports on A-A type organic small molecules, most of which are cyanines or D-A-D type structures. Therefore, this study has good exploratory significance and reference value for the discovery of NIR-II fluorophores.

This study aims to establish a primary rat hepatocyte culture model to evaluate dose-dependent hepatotoxic effects of drug carriers (lipopolymer nanoparticles; LPNs) temporal. Primary rat hepatocyte cell cultures were used to determine half-maximal Inhibition Concentrations (IC50) of the drug-carrier library. Drug-carrier library, at concentrations <50 μg/mL, is benign to primary rat hepatocytes as determined using albumin and urea secretions. Albumin, as a hepatic biomarker, exhibited a more sensitive and faster outcome, compared to urea, for the determination of the IC50 value of LPNs. Temporal measurements of hepatic biomarkers including urea and albumin, and rigorous physicochemical (hydrodynamic diameter, surface charge, etc.) characterization, should be combined to evaluate the hepatotoxicity of drug carrier libraries in screens.

Tumor-associated calcium signal transducer 2 (Trop2) is highly specific expressed in gastric carcinoma (GC). The combination of Trop2 antibody and phototherapy agents could exhibit synergetic antitumor activity. Black phosphorus nanosheets (BP) are covalently modified with Trop2 IgG antibodies via heterobifunctional linker of polyethylene glycol (PEG). Then the Trop2 antibody was directionally conjugated to BP via Schiff base reaction between aldehyde group from oxidized Trop2 antibody and amino group of PEG. The Trop2-functionalzied BP can significantly increase the endocytosis of BP in Trop2-positive GC cells exhibiting a reinforced antitumor activity under near infrared (NIR) irradiation. More importantly, a murine orthotopic GC model demonstrates that Trop2 antibody modification can significantly promote the accumulation of BP at tumor tissues and strengthen antitumoral activity of phototherapy. Directional conjugation of Trop2 antibody to BP facilitates the BP with superior stability, tumor targeting ability and excellent anti-tumor activity under NIR irradiation without systemic toxicity.

ObjectivePerineural invasion (PNI) is associated with local recurrence, distant metastasis, and a poor prognosis in pancreatic cancer. However, rare attempt was made to identified the PNI intraoperative. To facilitate precise R0 excision of the tumor, we planned to develop a fluorescent probe for intraoperative imaging of the PNI using GAP-43 as the target and indocyanine green (ICG) as the carrier.MethodsThe probe was created by binding peptide antibody and ICG. Its targeting was tested in vitro and in vivo using a co-culture model of PC12 and tumor cells to create an in vitro neural invasion model and a mouse sciatic nerve invasion model. The small animal imaging system and surgical navigation system confirmed the probe's potential clinical applicability. The sciatic nerve damage model was created to confirm the probe's targeting.ResultsWe used the pancreatic cancer samples and the public database to confirm that GAP-43 was preferentially overexpressed in pancreatic cancer, particularly in PNI. PC12 cells showed high GAP-43RA-PEG-ICG probe-specific absorption after being co-cultured with tumor cells in vitro. In the sciatic nerve invasion experiment, animals in probe group displayed a significantly stronger fluorescence signal at the PNI compared to ICG-NP and the contralateral normal nerves groups. Although only 60 % of mice appeared to have R0 resections by the naked eye, small animal imaging systems and surgical fluorescence navigation systems could remove the tumor with R0 precision. The injury model used in the probe imaging experimental trials demonstrated that the probe was specifically targeted to the injured nerve, regardless of whether the injury was infiltrated by a tumor or physical.ConclusionWe developed the GAP-43Ra-ICG-PEG, an active-targeting near-infrared fluorescent (NIRF) probe, that specifically binds to GAP-43-positive neural cells in an in vitro model of PNI. The probe efficiently visualized PNI lesions in pancreatic cancer in preclinical models, opening up new possibilities for NIRF-guided pancreatic surgery, particularly for PNI patients.

Repairing peripheral nerve injuries remains a challenge, even with use of auxiliary implantable biomaterial conduits. After implantation the location or function of polymeric devices cannot be assessed via clinical imaging modalities. Adding nanoparticle contrast agents into polymers can introduce radiopacity enabling imaging using computed tomography. Radiopacity must be balanced with changes in material properties impacting device function. In this study radiopaque composites were made from polycaprolactone and poly(lactide-co-glycolide) 50:50 and 85:15 with 0–40 wt% tantalum oxide (TaOx) nanoparticles. To achieve radiopacity, ≥5 wt% TaOx was required, with ≥20 wt% TaOx reducing mechanical properties and causing nanoscale surface roughness. Composite films facilitated nerve regeneration in an in vitro co-culture of adult glia and neurons, measured by markers for myelination. The ability of radiopaque films to support regeneration was driven by the properties of the polymer, with 5–20 wt% TaOx balancing imaging functionality with biological response and proving that in situ monitoring is feasible.

Urinary tract infections (UTIs) are among the most common bacterial infections. Despite a wide range of therapeutic options, treatment success is compromised by the efficient mechanism of tissue colonization of uropathogenic Escherichia coli. In advanced drug delivery systems, a similar, glycan-mediated targeting mechanism may be realized by conjugating the drug to a plant lectin, like wheat germ agglutinin (WGA).We introduce a drug delivery vehicle consisting of human serum albumin as nanoparticle shell, olive oil as core component, the active pharmaceutical ingredients (API) trimethoprim and rifampicin as well as WGA to facilitate cellular internalization. When WGA was embedded into the proteinaceous particle shell, cell binding studies revealed up to 60 % higher cell binding potential. Additionally, nanoparticles showed a good efficacy against gram-negative just as against gram-positive bacteria.The combination of the promising cell-associative properties and the proven antimicrobial potential might lead to an improved efficacy of advanced treatment of UTIs.

Oral cancer is a type of cancer that develops in the mouth and is one of the deadliest malignancies in the world. Currently surgical, radiation therapy, and chemotherapy are most common treatments. Better treatment and early detection strategies are required. Chemotherapeutic drugs fail frequently due to toxicity and poor tumor targeting. There are high chances of failure of chemotherapeutic drugs due to toxicity. Active, passive, and immunity-targeting techniques are devised for tumor-specific activity. Nanotechnology-based drug delivery systems are the best available solution and important for precise targeting. Nanoparticles, liposomes, exosomes, and cyclodextrins are nano-based carriers for drug delivery. Nanotechnology is being used to develop new techniques such as intratumoral injections, microbubble mediated ultrasonic therapy, phototherapies, and site-specific delivery. This systematic review delves into the details of such targeted and nano-based drug delivery systems in order to improve patient health and survival rates in oral cancer.

The devastating COVID-19 pandemic motivates the development of safe and effective antivirals to reduce morbidity and mortality associated with infection. We developed nanoscale liposomes that are coated with the cell receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. Lentiviral particles pseudotyped with the spike protein of SARS-CoV-2 were constructed and used to test the virus neutralization potential of the engineered liposomes. Under TEM, we observed for the first time a dissociation of spike proteins from the pseudovirus surface when the pseudovirus was purified. The liposomes potently inhibit viral entry into host cells by extracting the spike proteins from the pseudovirus surface. As the receptor on the liposome surface can be readily changed to target other viruses, the receptor-coated liposome represents a promising strategy for broad spectrum antiviral development.

Liver cancer such as hepatocellular carcinoma (HCC) poorly responds to chemotherapeutics as there are no effective means to deliver the drugs to liver cancer. Here we report GalNAc decorated exosomes as cargo for targeted delivery of Paclitaxel (PTX) and miR122 to liver tumors as an effective means to inhibit the HCC. Exosomes (Exos) are nanosized extracellular vesicles that deliver a payload to cancer cells effectively. GalNAc provides Exos targeting ability by binding to the asialoglycoprotein-receptor (ASGP-R) overexpressed on the liver cancer cell surface. A 4-way junction (4WJ) RNA nanoparticle was constructed to harbor 24 copies of hydrophobic PTX and 1 copy of miR122. The 4WJ RNA-PTX complex was loaded into the Exos, and its surface was decorated with GalNAc using RNA nanotechnology to obtain specific targeting. The multi-specific Exos selectively bind and efficiently delivered the payload into the liver cancer cells and exhibited the highest cancer cell inhibition due to the multi-specific effect of miR122, PTX, GalNAc, and Exos. The same was reflected in mice xenograft studies, the liver cancer was efficiently inhibited after systemic injection of the multi-specific Exos. The required effective dose of chemical drugs carried by Exos was significantly reduced, indicating high efficiency and low toxicity. The multi-specific strategy demonstrates that Exos can serve as a natural cargo vehicle for the targeted delivery of anticancer therapeutics to treat difficult-to-treat cancers.

This study aimed to compare the efficacy of neoadjuvant systemic therapy (NST) with solvent-based paclitaxel (Sb-P), liposomal paclitaxel (Lps-P), nanoparticle albumin-bound paclitaxel (Nab-P), and docetaxel in human epidermal growth factor receptor 2 (HER2)-low-positive and HER2-zero breast cancers. A total of 430 patients receiving 2-weekly dose-dense epirubicin and cyclophosphamide (EC) followed by 2-weekly paclitaxel (Sb-P, Lps-P, or Nab-P), or 3-weekly EC followed by 3-weekly docetaxel for NST were enrolled in the study. In HER2-low-positive patients, the pathological complete response (pCR) rate in Nab-P group was significantly higher than that in the other three paclitaxel groups (2.8 % in Sb-P group, 4.7 % in Lps-P group, 23.2 % in Nab-P group and 3.2 % in docetaxel group, p < 0.001). In HER2-zero patients, the pCR rate did not differ significantly among the four paclitaxel groups (p = 0.278). The NST regimen containing Nab-P could be considered a promising treatment option in HER2-low-positive breast cancer.

Rapamycin has great potential in the antitumor application, but its therapeutic effect is seriously affected by poor water solubility, targeting ability, and low bioavailability. Here, we constructed a novel composite nanomaterial with PCN-224 as a drug carrier and loaded rapamycin, named R@BP@HA. The nanoplate not only improves targeting, but also synergizes rapamycin with PCN-224 to effectively promote tumor cell apoptosis, which subsequently causes immunogenic cell death (ICD), and shows strong therapeutic effect in 4T1 breast cancer model. The treatment effect depends on three main points:(i)Proapoptotic effect of rapamycin on tumor cells;(ii)ROS production by PCN-224-mediated photodynamic therapy;(iii)ICD induced DC maturation, increased immune response and promoted T cell proliferation and differentiation. This nanoplate offers potential antitumor efficacy in combination with chemotherapy, photodynamic therapy, and immunotherapy.

Chemoresistance is the main cause of chemotherapy failure in ovarian cancer (OC). The enhanced scavenging of reactive oxygen species (ROS) by the thioredoxin system resulted in insufficient intracellular concentrations of effective ROS, leading to chemoresistance. To induce OC cell apoptosis by enhancing intracellular ROS levels, protoporphyrin IX (PpIX) and albumin-bound PTX nanoparticles (APNP) were utilized to fabricate APNP-PpIX nanoparticles. APNP-PpIX effectively generated ROS and increased the effective ROS concentration in chemoresistant cancer cells. The in vitro and in vivo experiments confirmed the effective inhibition of APNP-PpIX on chemoresistant OC cell proliferation and tumor formation. APNP-PpIX significantly improved the effectiveness of chemotherapy and photodynamic therapy, thus providing a new approach for the clinical treatment of chemoresistant OC.

Herein, we provide the first description of a synthetic delivery method for self-replicating replicon RNAs (RepRNA) derived from classical swine fever virus (CSFV) using a Coatsome-replicon vehicle based on Coatsome® SS technologies. This results in an unprecedented efficacy when compared to well-established polyplexes, with up to ∼65 fold-increase of the synthesis of RepRNA-encoded gene of interest (GOI). We demonstrated the efficacy of such Coatsome-replicon vehicles for RepRNA-mediated induction of CD8 T-cell responses in mice. Moreover, we provide new insights on physical properties of the RepRNA, showing that the removal of all CSFV structural protein genes has a positive effect on the translation of the GOI. Finally, we successfully engineered RepRNA constructs encoding a porcine reproductive and respiratory syndrome virus (PRRSV) antigen, providing an example of antigen expression with potential application to combat viral diseases. The versatility and simplicity of modifying and manufacturing these Coatsome-replicon vehicle formulations represents a major asset to tackle foreseeable emerging pandemics.

Peptosomes, as a vesicular polypeptide-based system and a versatile carrier for co-delivery of hydrophilic and hydrophobic materials, provide great delivery opportunities due to the intrinsic biocompatibility and biodegradability of the polypeptides backbone. In the current study, a novel poly(L-glutamic acid)-block-polylactic acid di-block copolymer (PGA-PLA) was synthesized in two steps. Firstly, γ-benzyl L-glutamate-N-carboxy anhydride (BLG-NCA) and 3,6-dimethyl-1,4-dioxane-2,5-dione were polymerized using N-hexylamine and benzyl alcohol as initiators to produce poly(γ-benzyl L-glutamate (PBLG) and polylactic acid. Then, PBLG was deprotected to produce PGA. Secondly, PGA was conjugated to the benzyl-PLGA to fabricate PGA-PLA diblock copolymer. The synthesized diblock copolymer was used for the encapsulation of doxorubicin, as hydrophilic anticancer and ultra-small superparamagnetic iron oxide nanoparticles (USPIONs) as hydrophobic contrast agent within aqueous core and bilayer of vesicular peptosome, respectively via double emulsion method. The prepared peptosomes (Pep@USPIONs-DOX) controlled the release of DOX (<15 % of the encapsulated DOX release up to 240 h of incubation at the physiological conditions) while increasing the stability and solubility of the hydrophobic USPIONs. Then, AS1411 DNA aptamer was decorated on the surface of the PGA-PLA peptosomes (Apt-Pep@USPIONs-DOX). The prepared targeted and non-targeted platforms showed spherical morphology with hydrodynamic sizes of 265 ± 52 and 229 ± 44 nm respectively. In vitro cellular cytotoxicity and cellular uptake were studied in nucleolin positive (4T1) and nucleolin negative (CHO) cell lines. Cellular uptake of the targeted formulation was greater than that of non-targeted peptosome, while cellular internalization of these peptosomes was identical in CHO cells. Moreover, targeted peptosomes showed greater toxicity than non-targeted peptosome in 4T1 cell line. The prepared theranostic targeted peptosomes demonstrated improved capability in terms of survival rate, biodistribution, tumor suppression efficiency, and MR imaging in the 4T1 tumor-bearing mice.

Tuberculosis (TB), historically the most significant cause of human morbidity and mortality, has returned as the top infectious disease worldwide, under circumstances worsened by the COVID-19 pandemic's devastating effects on public health. Although Mycobacterium tuberculosis, the causal agent, has been known of for more than a century, the development of tools to control it has been largely neglected. With the advancement of nanotechnology, the possibility of engineering tools at the nanoscale creates unique opportunities to exploit any molecular type. However, little attention has been paid to one of the major attributes of the pathogen, represented by the atypical coat and its abundant lipids. In this review, an overview of the lipids encountered in M. tuberculosis and interest in exploiting them for the development of TB control tools are presented. Then, the amalgamation of nanotechnology with mycobacterial lipids from both reported and future works are discussed.

Angiogenesis plays a key role in the progression and metastasis of melanoma, and the pro-angiogenic effect of macrophages is one major reason for the failure of current anti-angiogenic therapies. Here, a nano-immunotherapy combining ferumoxytol and poly(I:C) (ferumoxytol/poly(I:C)) has been developed to boost the anti-angiogenic activities of macrophages to inhibit melanoma. Our findings demonstrated that ferumoxytol/poly(I:C) was a highly efficacious anti-tumor therapy with limited toxicity. Both in vivo and in vitro experiments indicated that this combination was successful in impeding angiogenesis. Ferumoxytol/poly(I:C) was demonstrated to reduce the viability of endothelial cells, thus hindering tube formation. Particularly, ferumoxytol/poly(I:C) was able to polarize macrophages to the M1 phenotype and decrease the expression of vascular endothelial growth factor, which in turn amplified the anti-angiogenic properties of ferumoxytol/poly(I:C). This combination of ferumoxytol/poly(I:C) nano-immunotherapy enriches the anti-angiogenic therapeutic nature of ferumoxytol and will shed new light on the treatment of melanoma.

We investigated how the biodistribution of cannabidiol (CBD) within the central nervous system (CNS) is influenced by two different formulations, an oil-in-water (O/W) nanoemulsion and polymer-coated nanoparticles (PCNPs). We observed that both CBD formulations administered were preferentially retained in the spinal cord, with high concentrations reaching the brain within 10 min of administration. The CBD nanoemulsion reached Cmax in the brain at 210 ng/g within 120 min (Tmax), whereas the CBD PCNPs had a Cmax of 94 ng/g at 30 min (Tmax), indicating that rapid brain delivery can be achieved through the use of PCNPs. Moreover, the AUC0–4 h of CBD in the brain was increased 3.7-fold through the delivery of the nanoemulsion as opposed to the PCNPs, indicating higher retention of CBD at this site. Both formulations exhibited immediate anti-nociceptive effects in comparison to the respective blank formulations.