Nanoparticles For Delivery Research Articles

Chitosan-based self-healing thermosensitive hydrogel loaded with siHMGB1 for treatment of rheumatoid arthritis via macrophage repolarization.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease marked by immune cell activation, particularly macrophages. An imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages causes synovial inflammation and joint damage, worsening RA. This study presents a biomacromolecular hydrogel delivery system with apoferritin nanoparticles for effective delivery of small interfering high mobility group protein (siHMGB1). The system was designed to promote the polarization of M1 macrophages to the M2 phenotype by downregulating the HMGB1/TLR4/NF-κB-p65 signaling pathway, offering a potential therapeutic approach for the treatment of RA. The oxidized chondroitin sulfate - chitosan - sodium glycerol β - phosphate - Fn/siHMGB1 (OCF/siHMGB1) hydrogel system possessed temperature-sensitive and self-healing properties, enabling the sustained, stable, and efficient release of siHMGB1 at the affected joint. After effective uptake by macrophages, siHMGB1 could effectively repolarize M1-phenotype macrophages to M2-phenotype via the HMGB1/TLR4/NF-κB-p65 signaling pathway both in vitro and in vivo. Additionally, it suppressed the release of pro-inflammatory cytokines and upregulated anti-inflammatory cytokines, which significantly blocked the TLR4/p65-mediated inflammatory signaling. In conclusion, the siHMGB1-loaded hydrogel delivery system designed in this study is effective in treating RA and highlights the potential of gene therapy to induce repolarization of M1 to M2 macrophages for RA treatment.

Blood vessel wall shear stress determines regions of liposome accumulation in angiogenic vasculature.

Nanoparticles used for drug delivery often require intravenous administration exposing them to fluid forces within the vasculature, yet the impact of blood flow on nanoparticle delivery remains incompletely understood. Here, we utilized transgenic zebrafish embryos to investigate the relationship between the accumulation of fluorescently labeled PEGylated liposomes and various hemodynamic factors (such as flow velocity, wall shear stress (WSS), and flow pattern) across a wide range of angiogenic blood vessels. We reconstructed 3D models of vascular structures from confocal images and used computational fluid dynamics to calculate local WSS, velocities, and define flow patterns. The spatial distribution of fluorescently labeled liposomes was subsequently mapped within the same 3D space and correlated with local hemodynamic parameters. Through the integration of computational fluid dynamics and in vivo experimentation, we show that liposomes accumulated in vessel regions with WSS between 0.1-0.8 Pa, displaying an inverse linear correlation (R2 > 0.85) between time-averaged wall shear stress and liposome localization in vivo. Interestingly, flow pattern did not appear to impact liposome accumulation. Collectively, our findings suggest the potential of stealth liposomes for passive targeting of low-flow vasculature, including capillaries and intricate angiogenic vasculature resembling that of tumor vessel networks.

Encapsulation of Antarctic krill peptide by polysaccharide-based nanoparticles: Preparation, characterization, evaluation of stability and hypoglycemic activity

The aim of this study was to construct a chitosan quaternary ammonium salt (HTCC)/sodium alginate (SA) nanoparticle delivery system for the encapsulation of Antarctic krill peptide (AKP), with the goal of enhancing its stability and post-digestive hypoglycemic activity. Additionally, the effect of the content and encapsulation sequence of HTCC/SA on the structure and properties of AKP-loaded nanoparticles (AKP-loaded NPs) was investigated. As the content of the outermost wall material (HTCC) increased, the particle size of nanoparticles initially increased and then decreased. Concurrently, the zeta potential showed a trend of increase, ranging from -38.77 to 46.07 mV. When SA was used as the outermost wall material, the nanoparticles exhibited a smaller particle size (240.1 nm) and better dispersibility. Electrostatic interaction and hydrogen bonding were the major forces involved in the formation of AKP-loaded NPs. X-ray diffraction revealed that AKP was successfully encapsulated in an amorphous state. Scanning electron microscopy showed that AKP-loaded NPs had an elliptical or blocky appearance. Moreover, AKP-loaded NPs demonstrated good storage and temperature stability, while nanoparticles with HTCC in the outermost layer (HTCC:SA=2:1) showed good pH and ionic stability. During simulated digestion, AKP-loaded NPs inhibited the release of AKP in gastric fluid. Consequently, the hypoglycemic activity of digested AKP-loaded NPs was remarkably higher than unencapsulated AKP. Notably, the nanoparticles with HTCC in the outermost layer provided superior hypoglycemic activity. In summary, the polysaccharide-based delivery system exhibited great potential to improve the stability and post-digestive hypoglycemic activity of AKP, broadening its applications in the food and pharmaceutical industries.

Development, QbD-based optimisation, in-vivo pharmacokinetics, and ex-vivo evaluation of Eudragit® RS 100 loaded flurbiprofen nanoparticles for oral drug delivery.

This study aims to develop and evaluate flurbiprofen-loaded polymeric nanoparticles to achieve sustained drug release, enhancing therapeutic efficacy and minimising dosing frequency for improved patient outcomes. Flurbiprofen-loaded polymeric nanoparticles were prepared using a tubular microreactor and spray drying, optimised via Box-Behnken Design. Characterisation included particle size, encapsulation efficiency, in vitro and in vivo drug release, and techniques like FTIR, DSC, XRD, and SEM. Statistical analysis ensured robust formulation optimisation and evaluation of performance. The optimised batch of flurbiprofen-loaded polymeric nanoparticles was characterised for mean diameter, PDI, zeta potential, drug release, and EE% were found to be 306.1 ± 6.00 nm, 0.184 ± 0.02 Mw, -23.6 ± 1.51 mV, 85.46 ± 0.53% and 92.31 ± 0.84 (% w/w) respectively. Pharmacokinetic analysis further confirmed the sustained release, extending up to 12 hours and enhancing permeation compared to the pure flurbiprofen. Sustained release of flurbiprofen-loaded polymeric nanoparticles significantly enhances therapeutic effectiveness for inflammatory conditions.

The role of patient-specific variables in protein corona formation and therapeutic efficacy in nanomedicine.

Despite their potential, the adoption of nanotechnology in therapeutics remains limited, with only around eighty nanomedicines approved in the past 30years. This disparity is partly due to the "one-size-fits-all" approach in medical design, which often overlooks patient-specific variables such as biological sex, genetic ancestry, disease state, environment, and age that influence nanoparticle behavior. Nanoparticles (NPs) must be transported through systemic, microenvironmental, and cellular barriers that vary across heterogeneous patient populations. Key patient-dependent properties impacting NP delivery include blood flow rates, body fat distribution, reproductive organ vascularization, hormone and protein levels, immune responses, and chromosomal differences. Understanding these variables is crucial for developing effective, patient-specific nanotechnologies. The formation of a protein corona around NPs upon exposure to biological fluids significantly alters NP properties, affecting biodistribution, pharmacokinetics, cytotoxicity, and organ targeting. The dynamics of the protein corona, such as time-dependent composition and formation of soft and hard coronas, depend on NP characteristics and patient-specific serum components. This review highlights the importance of understanding protein corona formation across different patient backgrounds and its implications for NP design, including sex, ancestry, age, environment, and disease state. By exploring these variables, we aim to advance the development of personalized nanomedicine, improving therapeutic efficacy and patient outcomes.

Abstract A030: Beyond the LNP: Self-amplifying RNA with LION nanoformulation technology for development of safe and effective cancer therapeutics

Abstract HDT Bio, a Seattle biotech company, has developed a platform technology based on self-amplifying RNA and a proprietary nanoparticle delivery system. mRNA have been increasingly used in the development of vaccines in both infectious diseases and oncology. Especially LNP- delivered mRNA has been deployed, following the success during the COVID pandemic, However, self-ampliying RNA (repRNA) possesses several features of particular relevance to cancer medicine. HDT has developed a nanoparticle technology named LION[TM] to safely and effectively deliver RNA to patients. In vivo studies showed that repRNA not only is capable of delivering robust cell-mediated immune responses but also doing so with a significanlty improved safety profile compared to administration using LNP-based formulations. These data will be presented in the context of clinical safety data with repRNA/LION. Furthermore, repRNA/LION was siuccessfully used to induce robust T-cell responses against tumor antigens, and will be discussed. Citation Format: Peter Berglund. Beyond the LNP: Self-amplifying RNA with LION nanoformulation technology for development of safe and effective cancer therapeutics [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A030.

Anti-breast cancer effects of dairy protein active peptides, dairy products, and dairy protein-based nanoparticles

Breast cancer is the most frequently diagnosed and fatal cancer among women worldwide. Dairy protein-derived peptides and dairy products are important parts of the daily human diet and have shown promising activities in suppressing the proliferation, migration, and invasion of breast cancer cells, both in vitro and in vivo. Most of the review literature employs meta-analysis methods to explore the association between dairy intake and breast cancer risk. However, there is a lack of comprehensive summary regarding the anti-breast cancer properties of dairy protein-derived peptides, dairy products, and dairy protein-based nanoparticles as well as their underlying mechanisms of action. Therefore, the present study discussed the breast cancer inhibitory effects and mechanisms of active peptides derived from various dairy protein sources. Additionally, the characteristics, anti-breast cancer activities and active components of several types of dairy products, including fermented milk, yogurt and cheeses, were summarized. Furthermore, the preparation methods and therapeutic effects of various dairy protein-containing nanoparticle delivery systems for breast cancer therapy were briefly described. Lastly, this work also provided an overview of what is currently known about the anti-breast cancer effects of dairy products in clinical studies. Our review will be of interest to the development of natural anticancer drugs.

Low Molecular Weight Alginate Oligosaccharides as Alternatives to PEG for Enhancement of the Diffusion of Cationic Nanoparticles Through Cystic Fibrosis Mucus.

Airway mucus is a major barrier to the delivery of lipid-based nanoparticles in chronic airway diseases such as cystic fibrosis (CF). Receptor-Targeted Nanocomplexes (RTN), comprise mixtures of cationic lipids and bifunctional peptides with receptor-targeting and nucleic acid packaging properties. The aim of this study is to improve the mucus-penetrating properties of cationic siRNA and mRNA RTNs by combining them with low molecular weight alginate oligosaccharides, OligoG and OligoM. Cationic RTNs formulated with either alginate become strongly anionic, while PEGylated messenger RNA (mRNA) and short interfering RNA (siRNA) RTNs remain cationic. Both alginates enhance mucus diffusion rates of cationic siRNA and mRNA RTNs in a static mucus barrier diffusion model, with OligoG particularly effective. PEGylation also enhance mucus diffusion rates of siRNA RTNs but not mRNA RTNs. Electron microscopy shows that RTNs remained intact after mucosal transit. The transfection efficiency of OligoM-coated mRNA RTNs is better than those coated with OligoG or PEG, and similar to cationic RTNs. In siRNA RTN transfections, OligoM is better than OligoG although 1% PEG is slightly better than both. The combination of cationic RTNs and alginate oligosaccharides represents a promising alternative to PEGylation for epithelial delivery of genetic therapies across the mucus barrier while retaining transfection efficiency.

Core-shell upconversion nanoparticles with suitable surface modification to overcome endothelial barrier.

Upconversion nanoparticles (UCNPs), capable of converting near-infrared (NIR) light into high-energy emission, hold significant promise for bioimaging applications. However, the presence of tissue barriers poses a challenge to the effective delivery of nanoparticles (NPs) to target organs. In this study, we demonstrate the core-shell UCNPs modified with cationic biopolymer, i.e., N, N-trimethyl chitosan (TMC), can overcome endothelial barriers. The core-shell UCNP is composed of NaGdF4: Yb3+,Tm3+ (16.7 ± 2.7 nm) as core materials and silica (SiO2) shell. The average particle size of UCNPs@SiO2 is estimated at 26.1 ± 3.7 nm. X-ray diffraction (XRD), transmission electron microscopy (TEM) and element mapping shows the formation of hexagonal crystal structure of β-NaGdF4 and elements doping. The surface of UCNPs@SiO2 has been modified with poly(ethylene glycol) (PEG) to enhance water dispersibility and colloidal stability, and further modified with TMC with the zeta potential increasing from -2.1 ± 0.96 mV to 26.9 ± 12.6 mV. No significant toxic effect is imposed to HUVECs when the cells are treated with core-shell UCNPs with surface modification up to 250 µg/mL. The transport ability of the core-shell UCNPs has been evaluated by using the in vitro endothelial barrier model. Transepithelial electrical resistance (TEER) and immunofluorescence staining of tight junction proteins have been employed to verify the integrity of the in vitro endothelial barrier model. The results indicate that the transport percentage of the UCNPs@SiO2 with PEG and TMC through the model is up to 4.56%, which is twice higher than that of the UCNPs@SiO2 with PEG but without TMC and six times that of the UCNPs@SiO2.

Dual action tofacitinib-loaded PLGA nanoparticles alleviate colitis in an IBD mouse model.

Inflammatory bowel disease (IBD) affects over 7 million people worldwide and significant side effects are associated with current therapies such as tofacitinib citrate (TFC), which is linked to increased risks of malignancy and congestive heart issues. To mitigate these systemic adverse effects, localised drug delivery via nano-sized carriers to inflamed gut tissues represents a promising approach. Herein, we aimed to optimise the synthesis of nanoparticles (NPs) using a low molecular weight grade of Poly(lactic-co-glycolic acid) (PLGA) 50:50 loaded with TFC. This approach leverages the dual anti-inflammatory action of TFC and the local production of anti-inflammatory short-chain fatty acids from the degradation of PLGA by colonic gut microbiota. NPs were produced by nanoprecipitation and characterised for their drug release profile in vitro. The efficacy of the enhanced PLGA-TFC NPs was then tested in a C57BL/6 DSS colitis mouse model. The release profile of TFC from the enhanced PLGA NPs showed a 40% burst release within the first hour, followed by up to 80% drug release in the colonic environment. Notably, the degradation of PLGA by colonic gut microbiota did not significantly influence TFC release. In the mouse model, neither PLGA NPs alone nor TFC alone showed significant effects on weight loss compared to the TFC-loaded PLGA NPs, emphasising the enhanced efficacy potential of the combined formulation. Altogether, these results suggest a promising role of NP delivery systems in enhancing TFC efficacy, marking a significant step towards reducing dosage and associated side effects in IBD treatment. This study underscores the potential of PLGA-TFC NPs in providing targeted and effective therapy for IBD.

Biomimetic Nano-delivery of Small-Molecule Piceatannol Modulates Tumor Stemness and Suppresses Colorectal Cancer Metastasis via Hippo/YAP1/SOX9 Signaling.

Suppressing tumor metastasis is a crucial strategy for improving survival rates in patients with colorectal cancer (CRC), with cancer stem cells (CSCs) being the primary drivers of metastasis. Current therapeutic approaches targeting CSCs are limited, and their molecular mechanisms remain unclear. To address this challenge, a biomimetic nanoparticle delivery system, CMD-BHQ3-PTL/DOX@RBCM is developed, to deliver the stem cell regulator, piceatannol (PTL). This system used carboxymethyl dextran (CMD) and Black Hole Quencher 3 (BHQ3) to encapsulate PTL and the cytotoxic drug doxorubicin (DOX) within a red blood cell membrane (RBCm), enhancing stability and biocompatibility while allowing gradual drug release under hypoxic conditions. The effects of PTL are investigated on CSCs using molecular biology experiments, plasmid construction, and high-throughput sequencing and elucidated the molecular mechanisms underlying this biomimetic nanoparticle delivery system. The therapeutic efficacy of PTL is validated at the tissue level using subcutaneous and metastatic tumor models in human and murine systems. The results demonstrated that CMD-BHQ3-PTL/DOX@RBCM effectively addressed the challenges of specificity and biocompatibility in vivo, significantly inhibiting CSC-related tumor metastasis. This inhibitory effect is closely associated with the Hippo/YAP1/SOX9 pathway. This study highlights the effectiveness of the pH-responsive biomimetic nanoparticle system CMD-BHQ3-PTL/DOX@RBCm in delivering PTL to tumor sites, with SOX9 and its upstream Hippo/YAP1 pathway playing a critical role in the underlying mechanism.

Ultrasound-triggered nano delivery of lenvatinib for selective immunotherapy treatment against hepatocellular carcinoma

Although there have been remarkable advances in the treatment of hepatocellular carcinoma (HCC), the prognosis remains poor in those with advanced stage and more effective therapeutic options are urgently needed. Lenvatinib (Len), a multiple receptor tyrosine kinase inhibitor, is an emerging molecular targeted agent for HCC, whose immunomodulatory activities have been investigated. However, Len utilization is limited because of its low metabolic stability, poor bioavailability and dose-dependent toxicity, rendering its direct use insufficient for immune modulation. Stimuli-responsive nanoparticles, which are drug-targeted delivery platforms for on-demand drug release, facilitate deeper and uniform tumour penetration, providing alternative solutions to overcome current limitations. Ultrasound (US) exhibits superior tissue penetration abilities and can produce reactive oxygen species (ROS) at the tumour site to treat deeper tumours. In addition, US serves as an excellent and selective drug delivery mediator for tumour treatment. Herein, we designed US-triggered lenvatinib nanoparticles (Len-RNPs) for selective drug delivery that utilize US-triggered ROS to induce in situ oxidation reactions, resulting in nanoparticle disintegration. Len-RNPs mitigate the toxicity of Len and effectively trigger robust systemic anti-tumour immune responses in a H22 tumour model, resulting in a tumour suppression rate of 95.7%, with 60% of mice being cured. Our study elucidates a novel and precise strategy of combining Len and US therapy for enhanced HCC immunotherapy.

Enhancing Tumor Targeted Therapy: The Role of iRGD Peptide in Advanced Drug Delivery Systems

Chemotherapy remains the primary therapeutic approach in treating cancer. The tumor microenvironment (TME) is the complex network surrounding tumor cells, comprising various cell types, such as immune cells, fibroblasts, and endothelial cells, as well as ECM components, blood vessels, and signaling molecules. The often stiff and dense network of the TME interacts dynamically with tumor cells, influencing cancer growth, immune response, metastasis, and resistance to therapy. The effectiveness of the treatment of solid tumors is frequently reduced due to the poor penetration of the drug, which leads to attaining concentrations below the therapeutic levels at the site. Cell-penetrating peptides (CPPs) present a promising approach that improves the internalization of therapeutic agents. CPPs, which are short amino acid sequences, exhibit a high ability to pass cell membranes, enabling them to deliver drugs efficiently with minimal toxicity. Specifically, the iRGD peptide, a member of CPPs, is notable for its capacity to deeply penetrate tumor tissues by binding simultaneously integrins ανβ3/ανβ5 and neuropilin receptors. Indeed, ανβ3/ανβ5 integrins are characteristically expressed by tumor cells, which allows the iRGD peptide to home onto tumor cells. Notably, the respective dual-receptor targeting mechanism considerably increases the permeability of blood vessels in tumors, enabling an efficient delivery of co-administered drugs or nanoparticles into the tumor mass. Therefore, the iRGD peptide facilitates deeper drug penetration and improves the efficacy of co-administered therapies. Distinctively, we will focus on the iRGD mechanism of action, drug delivery systems and their application, and deliberate future perspectives in developing iRGD-conjugated therapeutics. In summary, this review discusses the potential of iRGD in overcoming barriers to drug delivery in cancer to maximize treatment efficiency while minimizing side effects.

Precision nanoparticles for drug delivery, cell therapy tracking, and theranostics

Precision nanoparticles for drug delivery, cell therapy tracking, and theranostics

Modified PEG-Lipids Enhance the Nasal Mucosal Immune Capacity of Lipid Nanoparticle mRNA Vaccines

Background/Objectives: Omicron, the predominant variant of SARS-CoV-2, exhibits strong immune-evasive properties, leading to the reduced efficacy of existing vaccines. Consequently, the development of versatile vaccines is imperative. Intranasal mRNA vaccines offer convenient administration and have the potential to enhance mucosal immunity. However, delivering vaccines via the nasal mucosa requires overcoming complex physiological barriers. The aim of this study is to modify PEGylated lipids to enhance the mucosal immune efficacy of the vaccine. Methods: The PEGylated lipid component of lipid nanoparticle (LNP) delivery vectors was modified with chitosan or mannose to generate novel LNPs that enhance vaccine adhesion or targeting on mucosal surfaces. The impact of the mRNA encoding the receptor-binding domain of Omicron BA.4/BA.5 on the immune response was examined. Results: Compared to the unmodified LNP group, the IgG and IgA titers in the chitosan or mannose-modified LNP groups showed an increasing trend. The chitosan-modified group showed better effects. Notably, the PEGylated lipid with 1.5 mol% of chitosan modification produced high levels of IgG1 and IgG2a antibodies, promoting Th1/Th2 responses while also generating high levels of IgA, which can induce stronger cellular immunity, humoral immunity, and mucosal immunity. Conclusions: The 1.5 mol% of chitosan-modified LNPs (mRNA-LNP-1.5CS) can serve as a safe and effective carrier for intranasal mRNA vaccines, offering a promising strategy for combating the Omicron variant.

A temperature-ultrasound sensitive nanoparticle delivery system for exploring central neuroinflammation mechanism in stroke-heart syndrome

BackgroundCardiovascular events secondary to stroke–collectively classified as stroke-heart syndrome–greatly impair the patient’s prognosis, however its underlying mechanism has yet to be determined. To investigate the mechanism of central neuroinflammation and its effects on stroke-heart syndrome, a temperature-ultrasound responsive brain-targeted drug delivery system, DATS/MION-LPE, was synthesized to specifically study neuroinflammation in the mouse middle cerebral artery occlusion (MCAO) model.ResultsThe specific polymer of DATS/MION-LPE can close the nanoparticle pores at 37 °C, restricting drug release in the circulation. After the nanoparticles were targeted to brains, the polymer can be cleaved under external ultrasound irradiation, reopening the nanoparticle pores and allowing drug release, therefore directly managing the neuroinflammation. After a stroke, a significant cerebral inflammation occurred, with elevated IL-1β and pyrin domain-containing 3 (NLRP3) inflammasome. Accordingly, significantly increased histone deacetylase 6 (HDAC6) and decreased sirtuin 1 (SIRT1) were observed. An antagonistic relationship between HDAC6 and SIRT1 was found, which can jointly regulate the cerebral NLRP3 expression. The systemic IL-1β and ATP levels were increased after the stroke, accompanied by a significant heart injury including contractile dysfunction, elevated IL-1β levels, and oxidative stress. Meanwhile, neuroinflammation can trigger sympathetic nervous overexcitation with associated heart damage. DATS/MION-LPE can targetedly effect on ischemic brain, exhibiting cerebral and cardiac protective effects including downregulated cerebral NLRP3 and HDAC6 expressions, upregulated SIRT1 expressions in brain, reduced IL-1β and ATP in circulation, and alleviated cardiac impairment.ConclusionThis study introduced the key role of neuroinflammation in stroke-heart syndrome and first investigated the crucial HDAC6/SIRT1-NLRP3 circuit in this process. Heart injury secondary to stroke is mediated by neuroinflammation induced systemic inflammatory responses and sympathoexcitation. DATS/MION-LPE is a unique tool and effective therapeutic agent, which provides new insights into combinational heart and cardiac protection.Graphical

Placental gene therapy in nonhuman primates: a pilot study of maternal, placental, and fetal response to non-viral, polymeric nanoparticle delivery of IGF1.

Currently, there are no placenta-targeted treatments to alter the in utero environment for administration to pregnant women who receive a diagnosis of fetal growth restriction (FGR). Water-soluble polymers have a distinguished record of clinical relevance outside of pregnancy. We have demonstrated the effective delivery of polymer-based nanoparticles containing a non-viral human insulin-like growth factor 1 (IGF1) transgene to correct placental insufficiency in small animal models of FGR. Our goals were to extend these studies to a proof-of-concept study in the pregnant macaque, establish feasibility of nanoparticle-mediated gene therapy delivery to trophoblasts, and investigate the acute maternal, placental, and fetal responses to treatment. Pregnant macaques underwent ultrasound-guided intraplacental injections of nanoparticles (GFP- or IGF1-expressing plasmid under the control of the trophoblast-specific PLAC1 promoter complexed with a HPMA-DMEAMA co-polymer) at approximately gestational day 100 (term = 165 days). Fetectomy was performed 24 h (GFP; n = 1), 48 h (IGF1; n = 3) or 10 days (IGF1; n = 3) after nanoparticle delivery. Routine pathological assessment was performed on biopsied maternal tissues and placental and fetal tissues. Maternal blood was analyzed for complete blood count (CBC), immunomodulatory proteins and growth factors, progesterone (P4), and estradiol (E2). Placental ERK/AKT/mTOR signaling was assessed using Western blot and qPCR. Fluorescent microscopy and in situ hybridization confirmed placental uptake and transient transgene expression in villous syncytiotrophoblast. No off-target expression was observed in either maternal or fetal tissues. Histopathological assessment of the placenta recorded observations not necessarily related to the IGF1 nanoparticle treatment. In maternal blood, CBCs, P4, and E2 remained within the normal range for pregnant macaques across the treatment period. Changes to placental ERK and AKT signaling at 48 h and 10 days after IGF1 nanoparticle treatment indicated an upregulation in placental homeostatic mechanisms to prevent overactivity in the normal pregnancy environment. The lack of adverse maternal reaction to nanoparticle-mediated IGF1 treatment, combined with changes in placental signaling to maintain homeostasis, indicates no deleterious impact of treatment during the acute phase of study.

Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor-Associated Macrophage.

Liver metastasis is the major cause of death in colorectal cancer (CRC) due to the lack of effective treatment. To explore novel drivers of CRC liver metastasis, the transcriptomes of primary paracancerous, colorectal tumors and metastases from human patients are profiled. It is found that SLIT- and NTRK-like family member 4 (SLITRK4) is the top upregulated gene in liver metastases and is associated with worse overall survival of CRC patients. Multiple in vitro and in vivo models suggested SLITRK4 promoted CRC tumorigenesis, invasion, migration, and angiogenesis, and inhibition of it restrained CRC tumor growth and liver metastasis with a more profound effect on the tumor microenvironment (TME). Mechanistically, SLITRK4 overexpression significantly activated the PI3K/AKT/NFκB pathway, regulated extracellular matrix organization, and multiple cytokines expression. Furthermore, the results from coculture models and single-cell RNA sequencing analyses suggested SLITRK4 promoted tumor-associated macrophages (TAMs) infiltration and polarization. In addition, macrophage depletion significantly inhibited SLITRK4-induced liver metastasis in CRC. Finally, pharmacological inhibition of SLITRK4 by using lipid-polymer hybrid nanoparticles (NPs) for systemic siRNA delivery can effectively inhibit CRC liver metastasis. Taken together, these results pinpoint that SLITRK4 regulates CRC tumorigenesis and liver metastasis, and siRNA delivering NPs agents validate the therapeutic potential of targeting SLITRK4 in CRC.

PEGylated Multimeric RNA Nanoparticles for siRNA Delivery in Traumatic Brain Injury.

Traumatic brain injury (TBI) impacts millions of people globally, however currently there are no approved therapeutics that address long-term brain health. In order to create a technology that is relevant for siRNA delivery in TBI after systemic administration, sub-100nm nanoparticles with rolling circle transcription (RCT) are synthesized and isolated in order improve payload delivery into the injured brain. Unlike conventional RCT-based RNA particles, in this method, sub-100nm RNA nanoparticles (RNPs) are isolated. To enhance RNP pharmacokinetics, RNPs are synthesized with modified bases in order to graft polyethylene glycol (PEG) to the RNPs. PEGylated RNPs (PEG-RNPs) do not significantly impact their knockdown activity in vitro and lead to longer blood half-life after systemic administration and greater accumulation into the injured brain in a mouse model of TBI. In order to demonstrate RNA interference (RNAi) activity of RNPs, knockdown of the inflammatory cytokine TNF-α in injured brain tissue after systemic administration of RNPs in a mouse model of TBI is demonstrated. In summary, small sub-100nm multimeric RNA nanoparticles are synthesized and isolated that can be modified using accessible chemistry in order to create a technology suitable for systemic RNAi therapy for TBI.

Nanoparticle-Based Nitric Oxide Donors: Exploring Their Antimicrobial and Anti-Biofilm Capabilities

Background: Nitric oxide (NO) is an antimicrobial and anti-biofilm agent with significant potential for combating biofilm-associated infections and antibiotic resistance. However, owing to its high reactivity due to the possession of a free radical and short half-life (1–5 s), the practical application of NO in clinical settings is challenging. Objectives: This review explores the development of NO-releasing nanoparticles that provide a controlled, targeted delivery system for NO, enhancing its antimicrobial efficacy while minimizing toxicity. The review discusses various NO donors, nanoparticle platforms, and how NO disrupts biofilm formation and eradicates pathogens. Additionally, we examine the highly encouraging and inspiring results of NO-releasing nanoparticles against multidrug-resistant strains and their applications in medical and environmental contexts. This review highlights the promising role of NO-based nanotechnologies in overcoming the challenges posed by increasing antibiotic resistance and biofilm-associated infections. Conclusions: Although NO donors and nanoparticle delivery systems show great potential for antimicrobial and anti-biofilm uses, addressing challenges related to controlled release, toxicity, biofilm penetration, resistance, and clinical application is crucial.