Search

The combination of the standard platinum-based chemotherapy with EGFR-tyrosine kinase inhibitor Gefitinib (Gef) principally boosts the anticancer efficacy of advanced non-small cell lung cancer (NSCLC) through non-overlapping mechanisms of action, however the clinical trials of cisplatin (Cis) and Gef combination failed to show a therapeutic improvement likely due to compromised cellular influx of Cis with the Gef interference. To overcome the antagonism between Cis and Gef in anti-NSCLC therapy, here we demonstrated a self-targeted hyaluronan (HA) nanogel to facilitate the anticancer co-delivery by utilizing the HA's intrinsic targeting towards CD44, a receptor frequently overexpressed on lung cancer cells. The co-assembly between HA, Cis and Gef generated a HA/Cis/Gef nanogel of 177.8 nm, featuring a prolonged drug release. Unlike the Gef inhibited the Cis uptake, the HA/Cis/Gef nanogel efficiently facilitated the drug internalization through CD44-targeted delivery as verified by HA competition and CD44 knocking down in H1975 NSCLC model both in vitro and in vivo. Moreover, the HA/Cis/Gef nanogel significantly improved the anticancer efficacy and meanwhile diminished the side effects in reference to the combination of free Cis and Gef. This CD44-targeted HA/Cis/Gef nanogel provided a potent strategy to advance the platinum-based combination therapy towards optimized NSCLC therapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The three-dimensional network architecture of hydrogels significantly influences their mechanical and physical properties; therefore, understanding them is essential for designing optimized hydrogel-based biomaterials. This study presents a comparative analysis of two hybrid hydrogels composed of konjac glucomannan (KGM) and kappa carrageenan (KCAR) with the same stiffness (5.2-5.7 kPa and 1.6-1.7 kPa) thus similar cross-linking density but different network architectures: a classic network formed by extended polysaccharide interactions and a nanogel junction network where nanoscale cross-linked KCAR (KCAR-NGs) links KGM chains. The mechanical behavior, dissolution, and diffusion characteristics were examined, revealing that the classic network demonstrates superior tensile resistance, elongation, and solvent-induced swelling resistance, leading to slower dissolution rates and higher viscosity. Conversely, the nanogel junction network offers higher permeability for small molecules and faster dissolution, suggesting a more open network structure. These findings highlight the nanogel-based hydrogels' advantages for biomedical applications requiring stability, permeability, and rapid dissolution without high temperatures or chelating agents. This study underscores the potential of nanogel junction networks to balance hydrogel stiffness and permeability, advancing the design of hydrogel-based biomaterials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nasal administration can bypass the blood-brain barrier and directly deliver drugs to the brain, providing a non-invasive route for central nervous system (CNS) diseases. Inspired by the appearance that a gate can block the outside world and the characteristics of the sol-gel transition can form a "gate" in the nasal cavity, a Drop to Gate nasal drop (DGND) is designed to set a gate in nose, which achieves protecting role from the influence of nasal environment. The DGND demonstrates the efficiency and application prospect of delivering drugs to the brain through the N-to-B. The effective concentration of single administration is increased through the hydrophobic interaction between C 8 -GelMA and SRT1720 (SA), and then cross-linked under UV to form nanogel, which can respond to MMP in the inflammatory microenvironment of sepsis-induced cognitive dysfunction. Finally, the SA/nanogel is compounded into the thermogel, which can respond to the nasal cavity temperature to form DGND in situ, increasing the residence time and delivery efficiency of drugs in the nasal cavity. In vitro, the DGND alleviates lipopolysaccharides (LPS)-induced BV2 inflammation. In vivo, DGND effectively targets the nasal mucosa and deliver drugs to the brain, which activate Sirt1 to alleviate inflammation mediated by microglia and improve cognitive dysfunction in sepsis mice., (© 2024 Wiley‐VCH GmbH.)

In this study, a novel magnetic and pH-responsive nanocarrier was developed, incorporating both natural and synthetic polymers, for delivering curcumin (CUR) to breast cancer cells. For this purpose, CuFe 2 O 4 @poly(methacrylic acid) (CuFe 2 O 4 @PMAA) nanogel was developed and conjugated with amino-modified lignin (Lignin-adipic acid dihydrazide conjugate, Lig-ADH) to achieve the CuFe 2 O 4 @PMAA@Lig-ADH nanocarrier. The morphology, structure, and physical properties of the synthesized nanomaterials were examined using a range of techniques, including transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), energy dispersive X-ray (EDX), and vibrating sample magnetometer (VSM). The synthesized nanocarrier exhibited a spherical shape, with an average diameter of approximately 15 nm, and demonstrated good magnetic responsiveness. Moreover, the in vitro drug release was found to be pH-dependent, with an increased release rate in acidic conditions. To evaluate cytotoxicity, the survival of MCF-7 cells was measured using the MTT assay for 24 h. Notably, the synthesized CuFe 2 O 4 @PMAA@Lig-ADH@CUR and CUR exhibited significant cytotoxic effects, effectively eliminating MCF-7 cells with IC 50 values of 39.80 µg/mL and 4.27 µg/mL, respectively. Also, the significant intracellular uptake of NPs was confirmed by FITC and DAPI staining after 4 h. This research highlighted the potential of CuFe 2 O 4 @PMAA@Lig-ADH@CUR as a highly effective nano-delivery system and demonstrated a straightforward method for utilizing renewable lignin., (© 2024. The Author(s).)

Appropriately modified thermoresponsive hydrogels, such as poly( N -isopropylacrylamide) hydrogels, bring an opportunity for a variety of biomedical applications. Incorporating compounds with different properties into poly( N -isopropylacrylamide) hydrogels offers opportunities to enhance their mechanical, self-healing ability, adhesiveness, thermal responsiveness, and drug release capabilities. In this study, we investigated the influence of Au-sulfur interactions on the properties of the poly( N -isopropylacrylamide) hydrogels after introducing N,N' -bis(acryloyl)cystine (a newly synthesized cross-linker), modified gold nanoparticles, and a p(NIPAm-BISS) nanogel into the hydrogel matrix. Our findings demonstrated that poly( N -isopropylacrylamide) hydrogels with these compounds exhibited higher mechanical strength (65% tensile stress and 25% elongation), faster thermal responsiveness, controllable self-healing [85% recovery after 2 min, using a NIR laser (800 nm, 0.75 W)], skin adhesiveness, and enhanced drug release (0.08 mg·mL -1 , a 93% improvement). These results may contribute to advancements in the design of temperature-responsive hydrogels tailored for specific biomedical needs, such as targeted drug delivery with the use of a NIR laser and tissue engineering.

The prospective of percutaneous drug delivery (PDD) mechanisms to address the limitations of oral and injectable treatment for rheumatoid arthritis (RA) is increasing. These limitations encompass inadequate compliance among patients and acute gastrointestinal side effects. However, the skin's intrinsic layer can frequently hinder the percutaneous dispersion of RA medications, thus mitigating the efficiency of drug delivery. To circumvent this constraint, we developed a strontium ranelate (SrR)-loaded alginate (ALG) phototherapeutic hydrogel to assess its effectiveness in combating RA. Our studies revealed that this SrR-loaded ALG hydrogel incorporating photoelectrically responsive molybdenum disulfide nanoflowers (MoS 2 NFs) and photothermally responsive polypyrrole nanoparticles (Ppy NPs) to form ALG@SrR-MoS 2 NFs-Ppy NPs demonstrated substantial mechanical strength, potentially enabling delivery of hydrophilic therapeutic agents into the skin and significantly impeding the progression of RA. Comprehensive biochemical, histological, behavioral, and radiographic analyses in an animal model of zymosan-induced RA demonstrated that the application of these phototherapeutic ALG@SrR-MoS 2 NFs-Ppy NPs effectively reduced inflammation, increased the presence of heat shock proteins, regulatory cluster of differentiation M2 macrophages, and alleviated joint degeneration associated with RA. As demonstrated by our findings, treating RA and possibly other autoimmune disorders with this phototherapeutic hydrogel system offers a distinctive, highly compliant, and therapeutically efficient method., (© 2024. The Author(s).)

Alginates are marine polysaccharides known for their ability to selectively bind calcium ions and form hydrogels. They are widely used in biomedical applications but are challenging to produce as nanogels. Here we introduce a self-assembly route to create stable alginate-based nanogels under near-equilibrium conditions. Guluronate (G) blocks, which interact with divalent cations such as Ca 2+ , Ba 2+ , and Sr 2+ , were extracted from alginates and covalently linked through their reducing end to the reducing end of dextran (Dex) chains, forming linear block copolymers that self-assemble into micellar nanogels with a core-corona structure in the presence of these ions. Real-time dynamic light scattering (DLS) and small-angle neutron scattering (SANS) were used to study the self-assembly mechanism of the copolymer during dialysis against divalent ions. For the G 12 - b -Dex 51 copolymer, we achieved spherical micelles with an 8 nm radius and an aggregation number of around 20. Although the type of divalent cation affected micelle stability, it did not influence their size. Micellar nanogels are dynamic structures, capable of ion exchange, and can disassemble with chelating agents like ethylenediamine tetraacetic acid (EDTA).

Respiratory syncytial virus (RSV) is one of the most significant pathogenic infections in childhood, associated with high morbidity and mortality rates. Currently, there is no effective and safe drug or vaccine available for RSV. Glycyrrhizic acid (GA), an active compound derived from the natural herb licorice, has been reported to provide protection against influenza and coronaviruses, exhibiting notable antiviral and anti-inflammatory properties. Ephedrine (EPH) is a commonly prescribed medication for the treatment of cough and asthma, and it also demonstrates certain antiviral effects. In this study, EPH and GA were combined to form an efficient nanomaterial (EPH-GA nanogel). The self-assembly of this nanogel is driven by hydrogen bonding and hydrophobic interactions, allowing it to serve as an antiviral nanomedicine without the need for a dual-component carrier, achieving a 100% drug loading efficiency. Oral administration of the EPH-GA nanogel significantly reduced viral load in the lungs of mice and improved lung lesions and tissue infiltration caused by RSV. Notably, we discovered that the assembled drug may create a "physical barrier" that prevents RSV from adsorbing to host cells, while free GA and EPH may compete with RSV for protein binding sites, thereby enhancing cellular uptake of EPH. Consequently, this prevents RSV infection and proliferation within host cells. Furthermore, the EC 50 values changed from 310.83 μM for EPH and 262.88 μM for GA to 68.25 μM for the EPH-GA combination, with a combination index of 0.458. In addition, the in vivo biopharmaceutic process of GA and EPH was investigated, revealing that the oral administration of EPH-GA significantly increased the bioavailability of EPH while maintaining its plasma concentration at a relatively stable level. This enhancement may contribute to a synergistic antiviral effect when combined with GA. Furthermore, the in vivo process of EPH-GA demonstrates the advantage of delivering the drug to the lesion at elevated levels, thereby facilitating its antiviral mechanism at the cellular level. In this study, we identified an effective nanomedicine, EPH-GA nanogel, which can inhibit the proliferation of RSV and mitigate lung lesions resulting from viral infection by influencing the biopharmaceutical process in vivo. This research not only offers a novel strategy for the nanomedicine treatment of RSV but also elucidates, to some extent, the compatibility mechanisms of the multicomponents of traditional Chinese medicine.

The functionalization approach for nanomaterials is of great importance for their application in drug delivery systems. Herein, an approach based on block copolymer installation into polymer nanogels was newly developed. Poly(vinyl alcohol)-incorporated polymer nanogels were prepared by a two-step dispersion/precipitation polymerization. Poly(methacrylic acid)- block -poly(3-fluorophenylboronic acid methacrylamide) (PMAA- b -PFPBMA) prepared by two-step reversible addition-fragmentation chain transfer polymerization was installed into the polymer nanogels via boronate ester formation. Furthermore, cisplatin as a cancer therapeutic drug was successfully loaded on the block copolymer-installed polymer nanogels, and cell death was achieved by using the resulting cisplatin-loaded nanogels. We believe that the functionality of the nanogels can be changed by varying the installed block copolymer, leading to the functionalization approach of polymer nanogels based on block copolymer installation, which will be of great utility in many fields.

A self-cleavable DNA nanogel loaded with splice-switch oligonucleotide (SSO) has been developed. Under acidic conditions (pH 5.0), cleavage of the acid-labile chemical linker and generation of the i-motif structure led to the disintegration of the DNA nanogel and efficient release of SSO in its unaltered native state.

This study details the preparation and investigation of molecular nanogels formed by the self-assembly of bolaamphiphilic dipeptide derivatives containing a reduction-sensitive disulfide unit. The described bolaamphiphiles, featuring amino acid terminal groups, generate cationic vesicles at pH 4, which evolve into gel-like nanoparticles at pH 7. The critical aggregation concentration has been determined, and the nanogels' size and morphology have been characterized through Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM). Circular Dichroism (CD) spectroscopy reveals substantial molecular reconfigurations accompanying the pH shift. These nanogels enhance the in vitro cellular uptake of the lipophilic dye Nile Red and the ionic photosensitizer Rose Bengal into Human colon adenocarcinoma (HT-29) cells, eliminating the need for organic co-solvents in the former case. Fluorescence measurements with Nile Red as a probe indicate the reduction-sensitive disassembly of the nanogels. In photodynamic therapy (PDT) applications, Rose Bengal-loaded nanogels demonstrate notable improvements, with flow cytometry analysis evidencing increased apoptotic activity in the study with HT-29 cells., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JUAN F. MIRAVET reports financial support was provided by Spanish Scientific Research Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Trinitroglycerin (TNG) with remarkable angiogenic, antibacterial, and antioxidative activity is a promising candidate to govern wound healing capacity. However, its clinical administration is limited due to associated complications and NO short half-life. In the current study, TNG-loaded chitosan nanogels (TNG-Ngs) were examined in-vitro and in-vivo to gain insight into their clinical application. We prepared TNG-Ngs and characterized their physiochemical properties. The potential of TNG-Ngs was assessed using biocompatibility, scratch assay, and a full-thickness skin wounds model, followed by histopathological and immunohistochemistry examinations. TNG-Ngs particle size 96 ± 18 and definite size distribution histogram. The loading capacity (LC) and encapsulation efficiency (EE) of prepared TNG-Ngs were 70.2 % and 2.1 %, respectively. The TNG-Ngs samples showed enhanced migration of HUVECs with no apparent cytotoxicity. The topical use of TNG-Ngs 200 on the wounds revealed a complete wound closure ratio, skin component formation, less scar width, remarkable granulation tissue, promoted collagen deposition, and enhanced the relative mean density of α-SMA and CD 31 . TNG-Ngs accelerated wound healing by promoting collagen deposition and angiogenic activity, as well as reducing inflammation. The findings indicated that TNG-Ngs is expected to be well vascularized in the wound area and to be more effective in topical therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Polyelectrolyte complexes (PECs) were elaborated from chitosan as cationic polymer and carboxy-methylpullulan (CMP), hyaluronic acid (HA) and their derivatives grafted with aminoguaiacol (G) with different degrees of substitution (DS GA ) with the aim of obtaining nanogels for drug delivery. For each couple of polysaccharides, the charge ratios giving the smaller size with the lower PDI were selected to produce PECs. CMP_CHIT and CMP-G_CHIT PECs had smaller sizes (220-280 nm) than HA_CHIT and HA-G_CHIT PECs (280-390 nm). PECs were stable at 4 °C during 28 days at pH 5. In phosphate buffer saline (PBS) at pH 7.4, at 4 °C, a better stability of PECs based on CMP-G derivatives was observed. The hydrophobic associations between aminoguaiacol groups (highlighted by measurements of pyrene fluorescence) led to a better PECs' stabilization in PBS. The PECs' antioxidant and antibacterial activities were demonstrated and related to the DS GA . Diclofenac and curcumin were used as drug models: their loading reached 260 and 53 μg/mg PEC, respectively. The release of diclofenac in PBS at 37 °C followed a quasi-Fickian diffusion mechanism with release constant between 0.88 and 1.04 h -1 . The curcumin release followed a slow linear increase in PBS/EtOH (60/40 V/V) with an effect of DS GA ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Hyaluronic acid (HA) based nanogels showed effective intracellular delivery efficacy for anti-cancer and anti-inflammatory drugs, characterized by their ability targeting relevant cell receptors. In the present study, we demonstrate the ability of hyaluronic acid-polyethyleneimine (HA-PEI) nanogels as a promising dual-functional interfacial active for intra-articular injection to intervene arthritis. Nanomechanical measurements on both model substrates and human cartilage samples confirm that the HA-PEI nanogels can significantly improve interfacial lubrication, in comparison to HA molecules, or silica-based nanoparticles. We show that the Coefficient of Friction significantly decreases with a decreasing nanogel size. The exceptional lubricating performance, coupled with the proven drug delivery capability, evidences the great potential of nanoscopic hydrogels for early-stage arthritis treatment. The flexibility in choosing the chemical nature, molecular architecture, and structural characteristics of nanogels makes it possible to modulate both drug delivery kinetics and interfacial lubrication, thus representing an innovative approach to treat degenerative joint diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Infection is one of the main causes of orthopedic implants failure, with antibiotic-resistant bacteria playing a crucial role in this outcome. In this work, antimicrobial nanogels were developed to be applied in situ as implant coating to prevent orthopedic-device-related infections. To that regard, a broad-spectrum antimicrobial peptide, Dhvar5, was grafted onto chitosan via thiol-norbornene "photoclick" chemistry. Dhvar5-chitosan nanogels (Dhvar5-NG) were then produced using a microfluidic system. Dhvar5-NG (10 10 nanogels (NG)/mL) with a Dhvar5 concentration of 6 μg/mL reduced the burden of the most critical bacteria in orthopedic infections - methicillin-resistant Staphylococcus aureus (MRSA) - after 24 h in medium supplemented with human plasma proteins. Transmission electron microscopy showed that Dhvar5-NG killed bacteria by membrane disruption and cytoplasm release. No signs of cytotoxicity against a pre-osteoblast cell line were verified upon incubation with Dhvar5-NG. To further explore therapeutic alternatives, the potential synergistic effect of Dhvar5-NG with antibiotics was evaluated against MRSA. Dhvar5-NG at a sub-minimal inhibitory concentration (10 9 NG/mL) demonstrated synergistic effect with oxacillin (4-fold reduction: from 2 to 0.5 μg/mL) and piperacillin (2-fold reduction: from 2 to 1 μg/mL). This work supports the use of Dhvar5-NG as adjuvant of antibiotics to the prevention of orthopedic devices-related infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Polysaccharides have garnered significant attention as potential nanoparticle carriers for targeted tumor therapy due to their excellent biodegradability and biocompatibility. Polyguluronic acid (PG) is a homogeneous acidic polysaccharide fragment derived from alginate, which is found in brown algae, possesses excellent bioactivities, unique properties. This study explored the immunomodulatory activity of PG and developed PG-based nanogels through modified disulfide bonds and Ca 2+ dual crosslinking. We characterized their structure, assessed their drug-loading and release properties, and ultimately validated both the safety of the nanocarrier and the in vitro anti-tumor efficacy of the encapsulated drug. Results indicated that PG significantly enhanced the proliferative activity and phagocytosis of RAW264.7 cells while promoting reactive oxygen species (ROS) production and cytokine secretion. The study identified TLR4 as the primary receptor for PG recognition in RAW264.7 cells. Furthermore, PG-based drug-carrying nanogels were prepared, exhibiting uniform sizes of about 184 nm and demonstrating exceptional encapsulation efficiency (82.15 ± 0.82 %) and drug loading capacity (8.12 ± 0.08 %). In vitro release experiments showed that these nanogels could responsively release drugs under conditions of high glutathione (GSH) reduction, facilitating drug accumulation at tumor sites and enhancing therapeutic efficacy. This research not only expands the application of PG in drug delivery systems but also provides valuable insights into leveraging natural immunomodulatory polysaccharides as carriers for targeted drug delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Modern drug delivery research focuses on developing biodegradable nanopolymer systems. The present study proposed a polymer-based composite nanogel as a transdermal drug delivery system for the pH-responsive targeted and controlled delivery of anticancer drug doxorubicin (DOX). Nanogels have properties of both hydrogels and nanomaterials. The β-cyclodextrin-based nanogels can enhance the loading capacity of poorly soluble drugs and promote a sustained drug release. The β-cyclodextrin-grafted methacrylic acid conjugated hyaluronic acid composite nanogel was successfully synthesized. β-Cyclodextrin was first grafted onto methacrylic acid. The composite nanogel-based drug carrier was prepared by controlled radical polymerization (CRP) of β-cyclodextrin-grafted methacrylic acid with hyaluronic acid. The doxorubicin-loaded carrier was characterized by Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, ultraviolet-visible (UV-vis) spectroscopy, zeta potential analysis, dynamic light scattering (DLS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The drug loading and release efficiencies were carried out at different pH levels. The maximum drug loading and encapsulation efficiencies of the synthesized final nanogel composite material at pH 8.0 were 86.44 ± 2.12 and 96.07 ± 2.01%, respectively. The DOX-loaded final material showed a 90.0 ± 2.6% release percentage of DOX at pH 5.5, whereas at pH 7.4, the release percentage of DOX was observed to be only 35.0 ± 0.3%. In vitro swelling, degradation, hemocompatibility, drug release kinetics, cytotoxicity, apoptosis, cell colocalization, skin irritation, and skin permeation studies, along with in vivo pharmacokinetic studies, were performed to prove the efficacy of the synthesized nanogel composite as a transdermal carrier for doxorubicin.

Age-related macular degeneration (AMD) is an eye disorder that can lead to visual impairment in elder patients, and current treatments include repeated injections of monoclonal antibody-based antivascular endothelial growth factor (anti-VEGF) agents. This study investigates the potential of a nanoformulation of a peptide anti-VEGF molecule for neovascular AMD. Anti-VEGF peptide HRHTKQRHTALH (HRH), which has high affinity to VEGF-Fc receptor, was used as the bioactive agent to control neovascularization of the retina. The nanoformulation consisting of hyaluronic acid nanogel was generated by incorporating divinyl sulfone and cholesterol to increase the stability and control the size of the nanodrug. The encapsulation efficacy of nanogel was 65%, and drug release was 34.72% at the end of 192 h. Obtained nanogels were efficiently internalized in 15 min by human umbilical vascular endothelial cells (HUVECs) and ARPE-19 cells, and results indicate that nanoformulation is not toxic to ARPE-19 cells, whereas it inhibits HUVEC proliferation owing to anti-VEGF peptide in the nanogel structure. In the coculture experiment in which retinal penetration was modeled, it was observed that the nanogel reached HUVECs and negatively affected their proliferation without disturbing the monolayer of ARPE-19 cells. In vivo experiments with chick chorioallantoic membrane revealed that nanogel formulation has higher antiangiogenesis activity compared to free HRH. Additionally, in an oxygen-induced retinopathy model, the excessive growth of blood vessels was notably suppressed in mice treated with HRH-loaded nanogel. This research indicates that nanogels formulated in this study are promising candidates as a topical treatment for AMD.

Nanomedicine has emerged as a promising avenue for advancing cancer treatment, but the challenge of mitigating its in vivo side effects necessitates the development of innovative structures and materials. Recent investigation has unveiled nanogels as particularly compelling candidates, characterized by a porous, three-dimensional network architecture that exhibits exceptional drug loading capacity. Beyond this, nanogels boast a substantial specific surface area and can be tailored with specific chemical functionalities. Consequently, nanogels are frequently engineered as a multi-modal synergistic platform for combating cancer, wherein photothermal therapy stands out due to its capacity to penetrate deep tissues and achieve localized tumor eradication through the application of elevated temperatures. In this review, we delve into the synthesis of diverse varieties of photothermal nanogels capable of controlled drug release triggered by either chemical or physical stimuli. It also summarizes their potential for synergistic integration with photothermal therapy alongside other therapeutic modalities to realize effective tumor ablation. Moreover, we analyze the primary mechanisms underlying the contribution of photothermal nanogels to cancer treatment while underscoring their adeptness in regulating therapeutic temperatures for repairing bone defects resulting from tumor-associated trauma. Envisioned as an auspicious strategy in the realm of cancer therapy, photothermal nanogels hold promise for furnishing controlled drug delivery and precise thermal ablation capabilities.

Effective drug delivery to bacterially infected mucosa remains a challenge due to the combined obstacles of the mucosal barrier, pH variations, and high concentrations of glutathione. However, polysaccharide-based responsive nanogels (NGs) can take advantage of these conditions to deliver specific antimicrobials. We explored the critical features of pH- and redox-responsive NGs to increase drug penetration, residence time, and efficacy in the infected mucosa. We prepared multifunctional NGs using hydroxypropyl cellulose as a template for the cross-linking of methacrylic acid with N , N '-bis(acryloyl)cystamine (BAC) or N , N '-methylenebis(acrylamide) (BIS). Studies of NG-mucin binding and the antibacterial efficacy of doxycycline-loaded NGs revealed the interplay between the response to pH and redox clues. Specifically, higher BAC composition increased mucus binding and controlled release in reductive conditions, while higher BIS composition yielded NGs with higher doxycycline-mediated antibacterial efficacy against Staphylococcus aureus . The findings reveal the potential of multiresponsive NGs in effective antimicrobial delivery in infected mucosa.

Rheumatoid arthritis (RA) involves chronic inflammation, oxidative stress, and complex immune cell interactions, leading to joint destruction. Traditional treatments are often limited by off-target effects and systemic toxicity. This study introduces a novel therapeutic approach using hyaluronic acid (HA)-conjugated, redox-responsive polyamino acid nanogels (HA-NG) to deliver tacrolimus (TAC) specifically to inflamed joints. The nanogels' disulfide bonds enable controlled TAC release in response to high intracellular glutathione (GSH) levels in activated macrophages, prevalent in RA-affected tissues. In vitro results demonstrated that HA-NG/TAC significantly reduced TAC toxicity to normal macrophages and showed high biocompatibility. In vivo, HA-NG/TAC accumulated more in inflamed joints compared to non-targeted NG/TAC, enhancing therapeutic efficacy and minimizing side effects. Therapeutic evaluation in collagen-induced arthritis (CIA) mice revealed HA-NG/TAC substantially reduced paw swelling, arthritis scores, synovial inflammation, and bone erosion while suppressing pro-inflammatory cytokine levels. These findings suggest that HA-NG/TAC represents a promising targeted drug delivery system for RA, offering potential for more effective and safer clinical applications., (© 2024. The Author(s).)

Management of urinary tract infections (UTI) is a highly challenging process due to the biofilm-forming ability of human-pathogenic bacteria. Here, we designed to fabricate an effective nanogel with a combination of chitosan bio-polymer and nalidixic acid to prevent biofilm-forming bacterial pathogens. Chitosan-coated nalidixic acid nanogel (NA@CS) exhibits outstanding inhibition potential against bacterial strains. In vitro, anti-bacterial analysis methods (well diffusion, colony-forming assay, and anti-biofilm assay) were performed to study the bacterial inhibition potential of prepared nanogel, which reveals that NA@CS nanogel have greater inhibition potential against selected pathogens. The combination of nalidixic acid with chitosan biopolymer decreases the virulence and pathogenicity of biofilm-forming pathogens due to their ability to membrane phospholipids penetration. Furthermore, the fabricated NA@CS nanogel showed reliable in vitro bio-compatibility on L929 fibroblast cells and in vivo compatibility with Artemia salina animal model. Overall, the results demonstrate that NA@CS nanogel could be an effective therapeutic for treating urinary tract infections and urine bladder wound healing., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To reduce the bitterness of florfenicol, avoid its degradation by gastric acid, and enhance its antibacterial activity against Escherichia coli by targeting and slowly releasing drugs at the site of intestinal infection, with pectin as an anion carrier and chitosan oligosaccharides (COS) as a cationic carrier, florfenicol-loaded COS@pectin core nanogels were self-assembled by electrostatic interaction and then encapsulated in sodium carboxymethylcellulose (CMCNa) shell nanogels through the complexation of CMCNa and Ca 2+ to prepare florfenicol core-shell composite nanogels in this study. The florfenicol core-shell composite nanogels were investigated for their formula choice, physicochemical characterization, pH-responsive performances, antibacterial activity, therapeutic efficacy, and in vitro and in vivo biosafety studies. The results indicated that the optimized formula was 0.6 g florfenicol, 0.79 g CMCNa, 0.30 g CaCl 2 , 0.05 g COS, and 0.10 g pectin, respectively. In addition, the mean particle diameter, polydispersity index, zeta potential, loading capacity, and encapsulation efficiency were 124.0 ± 7.2 nm, -22.9 ± 2.5 mV, 0.42 ± 0.03, 43.4 % ± 3.1 %, and 80.5 % ± 3.4 %, respectively. The appearance, lyophilized mass, resolvability, scanning electron microscopy (SEM), transmission electron microscopy (TEM), powder X-ray diffraction (PXRD), and fourier transform infrared (FTIR) showed that the florfenicol core-shell composite nanogels were successfully prepared. Florfenicol core-shell composite nanogels had satisfactory stability, rheology, and pH-responsiveness, which were conducive to avoid degradation by gastric acid and achieve targeted and slow release at intestinal infection sites. More importantly, florfenicol core-shell composite nanogels had excellent antibacterial activity against Escherichia coli, a satisfactory therapeutic effect, and good palatability. In vitro and in vivo biosafety studies suggested the great promise of florfenicol core-shell composite nanogels. Therefore, the prepared florfenicol core-shell composite nanogels may be helpful for the treatment of bacterial enteritis as a biocompatible oral administration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The ubiquitous mold Aspergillus fumigatus (A. fumigatus) is one of the main fungal pathogens causing invasive infections in immunocompromised humans. Conventional antifungal agents exhibit limited efficacy and often cause severe side effects. Nanoparticle-based antifungal delivery provides a promising alternative, which can increase local drug concentration; while, mitigating toxicity, thereby enhancing treatment efficacy. Previous research underscores the potential of poly(glycidol)-based nanogels (NG) with negative surface charge as carriers for delivering antifungals to A. fumigatus hyphae. In this study, NG is tailored with 2-carboxyethyl acrylate (CEA) or with phosphoric acid 2-hydroxyethyl acrylate (PHA). It is discovered that quenching with PHA clearly improves the adhesion of NG to hyphal surface and the internalization of NG into the hyphae under protein-rich conditions, surpassing the outcomes of non-quenched and CEA-quenched NG. This enhancement cannot be solely attributed to an increase in negative surface charge but appears to be contingent on the functional group of the quencher. Further, it is demonstrated that itraconazole-loaded, PHA-functionalized nanogels (NGxPHA-ITZ) show lower MIC in vitro and superior therapeutic effect in vivo against A. fumigatus compared to pure itraconazole. This confirms NGxPHA as a promising antifungal delivery system., (© 2024 The Author(s). Macromolecular Bioscience published by Wiley‐VCH GmbH.)

Intra-articular injection of drugs is an effective strategy for osteoarthritis (OA) treatment. However, the complex microenvironment and limited joint space result in rapid clearance of drugs. Herein, a nanogel-based strategy is proposed for prolonged drug delivery and microenvironment remodeling. Nanogel is constructed through the functionalization of hyaluronic acid (HA) by amide reaction on the surface of Kartogenin (KGN)-loaded zeolitic imidazolate framework-8 (denoted as KZIF@HA). Leveraging the inherent hydrophilicity of HA, KZIF@HA spontaneously forms nanogels, ensuring extended drug release in the OA microenvironment. KZIF@HA exhibits sustained drug release over one month, with low leakage risk from the joint cavity compared to KZIF, enhanced cartilage penetration, and reparative effects on chondrocytes. Notably, KGN released from KZIF@HA serves to promote extracellular matrix (ECM) secretion for hyaline cartilage regeneration. Zn 2+ release reverses OA progression by promoting M2 macrophage polarization to establish an anti-inflammatory microenvironment. Ultimately, KZIF@HA facilitates cartilage regeneration and OA alleviation within three months. Transcriptome sequencing validates that KZIF@HA stimulates the polarization of M2 macrophages and secretes IL-10 to inhibit the JNK and ERK pathways, promoting chondrocytes recovery and enhancing ECM remodeling. This pioneering nanogel system offers new therapeutic opportunities for sustained drug release, presenting a significant stride in OA treatment strategies., (© 2024 Wiley‐VCH GmbH.)

Transcatheter arterial chemoembolization (TACE) is the first-line therapy for hepatocellular carcinoma (HCC). However, the exacerbated hypoxia microenvironment induces tumor relapse and metastasis post-TACE. Here, temperature-sensitive block polymer complexed with polyphosphate-cisplatin (Pt-P@PND) was prepared for the enhancement of tumor artery embolization by coagulation activation. After supra-selective infusion into the tumor vessels, Pt-P@PND nanogels performed efficient embolization of tumor arteries by sol-gel transition at body temperature. Meanwhile, coagulation cascade was evoked to form blood clots in the peripheral arteries inaccessible to the nanogels by released PolyP. The blood clots-filled hydrogel networks composed of gel and clots showed a denser structure and higher modulus, thereby achieving long-term embolization of all levels of tumor arteries. Pt-P@PND nanogels efficiently inhibited tumor growth and reduced the expression of HIF-1α, VEGF, CD31, and MMP-9 on VX2 tumor-bearing rabbit model. The released Nitro-Pt stimulated the immunogenic cell death of tumor cells, thus enhancing the antitumor immune response to suppress tumor relapse and metastasis post-TACE. It is hoped that Pt-P@PND nanogels can be developed as a promising embolic agent with procoagulant activity for enhancing the antitumor immune response through a combination of embolism, coagulation, and chemotherapy. STATEMENT OF SIGNIFICANCE: Clinical embolic agents, such as Lipiodol and polyvinyl alcohol (PVA) microspheres, are limited by their rapid elimination or larger size, thus lead to incomplete embolization of trans-catheter arterial chemoembolization (TACE). Herein, temperature-sensitive Pt-P@PND nanogels were developed to achieve long-term embolization of all levels of tumor arteries by gel/clot generation. The released Nitro-Pt induced immunogenic cell death in tumor cells, which improved the antitumor immune microenvironment by the maturation of DCs and lymphocytic infiltration. Pt-P@PND nanogels successfully inhibited tumor growth and activated an antitumor immune response to curb the recurrence and metastasis of residual tumor cells both in VX2 tumor-bearing rabbit model and 4T1 tumor-bearing mouse model. These findings suggested that Pt-P@PND could be developed as an ideal embolic agent for clinical TACE treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Effectively addressing retinal issues represents a pivotal aspect of blindness-related diseases. Novel approaches involving reducing inflammation and rebalancing the immune response are paramount in the treatment of these conditions. This study delves into the potential of a nanogel system comprising polyethylenimine-benzene boric acid-hyaluronic acid (PEI-PBA-HA). We have evaluated the collaborative impact of cerium oxide nanozyme and chemokine CX3CL1 protein for targeted immunomodulation and retinal protection in uveitis models. Our nanogel system specifically targets the posterior segment of the eyes. The synergistic effect in this area reduces oxidative stress and hampers the activation of microglia, thereby alleviating the pathological immune microenvironment. This multifaceted drug delivery system disrupts the cycle of oxidative stress, inflammation, and immune response, suppressing initial immune cells and limiting local retinal structural damage induced by excessive immune reactions. Our research sheds light on interactions within retinal target cells, providing a promising avenue for the development of efficient and innovative drug delivery platforms., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In the study, we have shown the efficacy of an indigenously developed redox balancing chitosan gel with impregnated citrate capped Mn 3 O 4 nanoparticles (nanogel). Application of the nanogel on a wound of preclinical mice model shows role of various signaling molecules and growth factors, and involvement of reactive oxygen species (ROS) at every stage, namely hemostasis, inflammation, and proliferation leading to complete maturation for the scarless wound healing. While in vitro characterization of nanogel using SEM, EDAX, and optical spectroscopy reveals pH regulated redox buffering capacity, in vivo preclinical studies on Swiss albino involving IL-12, IFN-γ, and α-SMA signaling molecules and detailed histopathological investigation and angiogenesis on every stage elucidate role of redox buffering for the complete wound healing process., (© 2024 Wiley Periodicals LLC.)

Fluoride and aluminum are ubiquitous toxic metals with adverse reproductive effects. The citrus flavonoid hesperidin has protective activities but poor solubility and bioavailability. Nanoparticulate delivery systems can improve flavonoid effectiveness. We conducted this study to prepare a pH-responsive chitosan-based nanogel for hesperidin delivery and evaluate its effectiveness against sodium fluoride (NaF) and aluminum chloride (AlCl 3 ) induced testicular toxicity in mice. The nanogel was synthesized using 2 kGy gamma irradiation, enabling a size under 200 nm and enhanced hesperidin release at pH 6 matching testicular acidity. Male mice received 200 mg/kg AlCl 3 and 10 mg/kg NaF daily for 30 days. Hesperidin nanogel at 20 mg/kg was administered orally either prophylactically (pretreatment) or after intoxication (posttreatment). The results showed that AlCl 3  + NaF induced severe oxidative stress, hormonal disturbance, apoptosis, and endoplasmic reticulum stress, evidenced by significant changes in the studied parameters and testicular histological damage. Hesperidin nanogel administration significantly inhibited oxidative stress markers, restored luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels, and alleviated tissue damage compared to the intoxicated group. It also downregulated the expression level of pro-apoptotic genes Bax, caspase-3, caspase-9, and P38MAPK, while upregulating the expression level of the anti-apoptotic BCL2 gene. Endoplasmic reticulum stress sensors PERK, ATF6, and IRE-α were also downregulated by the nanogel. The chitosan-based nanogel enhanced the delivery and efficacy of poorly bioavailable hesperidin, exhibiting remarkable protective effects against AlCl 3 and NaF reproductive toxicity. This innovative nanosystem represents a promising approach to harnessing bioactive phytochemicals with delivery challenges, enabling protective effects against chemical-induced testicular damage., (© 2023. The Author(s).)

Radiofrequency-responsive nanoparticles (RFNPs) have drawn increasingly attentions as RF energy absorbing antenna to enhance antitumor efficacy of radiofrequency ablation (RFA). However, it remains a huge challenge for inorganic RFNPs to precisely synergize RFA with other antitumor modes in a clinically acceptable way on bio-safety and bio-compatibility. In this work, RF-responsive black phosphorus (BP) nanogel (BP-Pt@PNA) was successfully fabricated by crosslinking coordination of cisplatin with BP and temperature sensitive polymer PNA. BP-Pt@PNA exhibited strong RF-heating effect and RF-induced pulsatile release of cisplatin. Under RF irradiation, BP-Pt@PNA exhibited cytotoxic enhancement on 4T1 cells. By the synergistic effect of BP and cisplatin, BP-Pt@PNA achieved RF-stimulated systemic immune effect, thus induced enhance suppression on tumor growth and metastasis. Moreover, BP-Pt@PNA realized long-term drug retention in tumor and favorable embolization to tumor-feeding arteries. With high drug loading capacity and favorable bio-safety and bio-degradability, BP-Pt@PNA is expected as an ideal RFNP for precisely synergizing RFA with other antitumor modes in clinical application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chemodynamic therapy (CDT) is emerging as a promising treatment for biofilm infections. However, its effectiveness is significantly hindered by several factors: the body's stable temperature, a limited supply of Fe 2+ ions, and inadequate endogenous levels of H 2 O 2 at the infection sites. Herin, our study introduces MPN-crosslinked hyaluronic acid (HA) nanogels as an effective strategy for treating biofilm-associated infections. The DHA@HA-TA/Fe (DHTF) nanogel is synthesized through the coordination reaction between Fe 2+ ions and tannic acid (TA)-modified HA, with dihydroartemisinin (DHA) encapsulated within the structure. DHTF exhibits pH-/hyaluronidase-responsiveness in the biofilm infection microenvironment, enabling sustained release of DHA as a substitute for H 2 O 2 and Fe 2+ for CDT. The incorporation of Fe 2+ /TA-based MPN and DHA within the nanogels enables photothermal/DHA dually-enhanced CDT, facilitating efficient disruption of biofilm matrices and bacterial eradication through boosting reactive oxygen species production. In vivo studies demonstrate that DHTF exhibit prolonged retention within biofilms. This ensures a sustained release of therapeutic agents and continuous anti-biofilm activity. Eventually, both in vitro and in vivo evaluations consistently confirm the significant anti-biofilm capacity of DHTF. Our findings highlight the potential of DHTF as a promising nanomedicine for biofilm-related infections, offering efficient treatment strategies that could improve clinical management of these challenging conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study investigates the extract of the bioactive compounds from green coffee extract (GCE) and the loading of two different concentrations of GCE (1% and 2%) onto carrageenan nanogels (CAR NGs) to compare their antibacterial and antibiofilm effects with unloaded nanogels (NGs). The bioactive compounds of GCE were characterized using GC-MS analysis. The GCE1 and GCE2 were successfully deposited onto the surface of CAR NGs. The antibacterial and antibiofilm potential of prepared NGs were conducted against some foodborne pathogens (E. coli O157, Salmonella enterica, Staphylococcus aureus, and Listeria monocytogenes). The results of GC-MS analysis indicated that there were identified 16 bioactive compounds in GCE, including caffeine (36.27%), Dodemorph (9.04%), and D-Glycero-d-ido-heptose (2.44%), contributing to its antimicrobial properties. The antibacterial coatings demonstrated a notable antimicrobial effect, showing zone of inhibition (ZOI) diameters of up to 37 mm for GCE2 loaded CAR NGs. The minimum inhibitory concentration (MIC) values for GCE2 loaded CAR NGs were 80 ppm for E. coli O157, and 120 ppm for S. enterica, S. aureus, and L. monocytogenes, achieving complete bacterial inactivation within 10-15 min of exposure. Both GCE1 and GCE2 loaded CAR NGs significantly reduced biofilm cell densities on stainless steel (SS) materials for E. coli O157, S. enterica, S. aureus, and L. monocytogenes, with reductions ranging from 60% to 95%. Specifically, biofilm densities were reduced by up to 95% for E. coli O157, 89% for S. enterica, 85% for S. aureus, and 80% for L. monocytogenes. Results of the toxicity evaluation indicated that the NGs were non-toxic and biocompatible, with predicted EC 50 values proved their biocompatibility and safety. These results recommended that GCE loaded CAR NGs are promising as natural antimicrobial agents for enhancing food safety and extending shelf life. Further, the study concluded that incorporating GCE into CAR NGs is an effective strategy for developing sustainable antimicrobial coatings for the food industry and manufacturing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Co-delivery of different protein-encoding polynucleotide species with varying expression kinetics of their therapeutic product will become a prominent requirement in the realm of combined nucleic acid(NA)-based therapies in the upcoming years. The current study explores the capacity for time-staggered expression of encoded proteins by simultaneous delivery of plasmid DNA (pDNA) in the core and mRNA on the shell of the same nanocarrier. The core is based on a Gelatin Type A-pDNA coacervate, thermally stabilized to form an irreversible nanogel stable enough for the deposition of cationic coats namely, protamine sulfate or LNP-related lipid mixtures. Only the protamine-coated nanocarriers remained colloidally stable following mRNA loading and could successfully co-transfect murine dendritic cell line DC2.4 with fluorescent reporter mRNA(mCherry) and pDNA (pAmCyan1). Further investigation of the protamine-coated nanosystem only, the transfection efficiency (percentage of transfected cells) and level of protein expression (mean fluorescence intensity, MFI) of mRNA and pDNA, simultaneously delivered by the same nanocarrier, were compared and kinetically assessed over 48 h in DC2.4 using flow cytometry. The onset of transfection for both nucleotides was initially delayed, with levels < 5% at 6 h. Thereafter, mRNA transfection reached 90% after 24 h and continued to slightly increase until 48 h. In contrast, pDNA transfection was clearly slower, reaching approximately 40% after 24 h, but continuing to increase to reach 94% at 48 h. The time course of protein expression (represented by MFI) for both NAs essentially followed that of transfection. Model-independent as well as model-dependent kinetic parameters applied to the data further confirmed such time-staggered expression of the two NA's where mRNA's rate of transfection and protein expression initially exceeded those of pDNA in the first 24 h of the experiment whereas the opposite was true during the second 24 h of the experiment where pDNA displayed the higher response rates. We expect that innovative nanocarriers capable of time-staggered co-delivery of different nucleotides could open new perspectives for multi-dosing, pulsatile or sustained expression of nucleic acid-based therapeutics in protein replacement, vaccination, and CRISPR-mediated gene editing scenarios., (© 2024. Controlled Release Society.)

Hyperthermia and chemotherapy represent potential modalities for cancer treatments. However, hyperthermia can be invasive, while chemotherapy drugs often have severe side effects. Recent clinical investigations have underscored the potential synergistic efficacy of combining hyperthermia with chemotherapy, leading to enhanced cancer cell killing. In this context, magnetic iron oxide nanogels have emerged as promising candidates as they can integrate superparamagnetic iron oxide nanoparticles (IONPs), providing the requisite magnetism for magnetic hyperthermia, with the nanogel scaffold facilitating smart drug delivery. This review provides an overview of the synthetic methodologies employed in fabricating magnetic nanogels. Key properties and designs of these nanogels are discussed and challenges for their translation to the clinic and the market are summarised.

The challenges posed by intractable relapse and metastasis in cancer treatment have led to the development of various forms of photodynamic therapy (PDT). However, traditional drug delivery systems, such as virus vectors, liposomes, and polymers, often suffer from issues like desynchronized drug release, carrier instability, and drug leakage during circulation. To address these problems, we have developed a dual-prodrug nanogel (PVBN) consisting of Pyro (Pyropheophorbide a) and SAHA (Vorinostat) bound to BSA (Bovine Serum Albumin), which facilitates synchronous and spontaneous drug release in situ within the lysosome. Detailed results indicate that PVBN-treated tumor cells exhibit elevated levels of ROS and Acetyl-H3, leading to necrosis, apoptosis, and cell cycle arrest, with PDT playing a dominant role in the synergistic therapeutic effect. Furthermore, the anti-tumor efficacy of PVBN was validated in melanoma-bearing mice, where it significantly inhibited tumor growth and pulmonary metastasis. Overall, our dual-prodrug nanogel, formed by the binding of SAHA and Pyro to BSA and releasing drugs within the lysosome, represents a novel and promising strategy for enhancing the clinical efficacy of photochemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We describe a facile method to prepare water-compatible molecularly imprinted polymer nanogels (MIP NGs) as synthetic antibodies against target glycans. Three different phenylboronic acid (PBA) derivatives were explored as monomers for the synthesis of MIP NGs targeting either α2,6- or α2,3-sialyllactose, taken as oversimplified models of cancer-related sT and sTn antigens. Starting from commercially available 3-acrylamidophenylboronic acid, also its 2-substituted isomer and the 5-acrylamido-2-hydroxymethyl cyclic PBA monoester derivative were initially evaluated by NMR studies. Then, a small library of MIP NGs imprinted with the α2,6-linked template was synthesized and tested by mobility shift Affinity Capillary Electrophoresis (msACE), to rapidly assess an affinity ranking. Finally, the best monomer 2-acrylamido PBA was selected for the synthesis of polymers targeting both sialyllactoses. The resulting MIP NGs display an affinity constant≈10 6  M -1 and selectivity towards imprinted glycans. This general procedure could be applied to any non-modified carbohydrate template possessing a reducing end., (© 2024 Wiley-VCH GmbH.)

Stimulating the release of small nanoparticles (NPs) from a larger NP via the application of an exogenous stimulus offers the potential to address the different size requirements for circulation versus penetration that hinder chemotherapeutic drug delivery. Herein, we report a size-switching nanoassembly-based drug delivery system comprised of ultrasmall starch nanoparticles (SNPs, ∼20-50 nm major size fraction) encapsulated in a poly(oligo(ethylene glycol) methyl ether methacrylate) nanogel (POEGMA, ∼150 nm major size fraction) cross-linked via supramolecular PEG/α-cyclodextrin (α-CD) interactions. Upon heating the nanogel using a non-invasive, high-intensity focused ultrasound (HIFU) trigger, the thermoresponsive POEGMA-CD nanoassemblies are locally de-cross-linked, inducing in situ release of the highly penetrative drug-loaded SNPs. HIFU triggering increased the release of nanoassembly-loaded DOX from 17 to 37% after 3 h, a result correlated with significantly more effective tumor killing relative to nanoassemblies in the absence of HIFU or drug alone. Furthermore, 1.5× more total fluorescence was observed inside a tumor spheroid when nanoassemblies prepared with fluorophore-labeled SNPs were triggered with HIFU relative to the absence of HIFU. We anticipate this strategy holds promise for delivering tunable doses of chemotherapeutic drugs both at and within a tumor site using a non-invasive triggering approach.

Asthma is a chronic and heterogeneous disease affecting the lungs and respiratory tract. In particular, the neutrophil subtype of asthma was described as persistent, more severe, and corticosteroid-resistant. Growing evidence suggested that nontypeable Haemophilus influenzae (NTHi) infection contributes to the development of neutrophilic asthma, exacerbating clinical symptoms and increasing the associated medical burden. In this work, arginine-grafted chitosan (CS-Arg) was ionically cross-linked with tris(2-carboxyethyl) phosphine (TCEP), and a highly-efficient antimicrobial agent, poly-ε-L-Lysine (ε-PLL), was incorporated to prepare ε-PLL/CS-Arg/TCEP (ECAT) composite nanogels. The results showed that ECAT nanogels exhibited highly effective inhibition against the proliferation of NTHi, Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). In addition, ECAT nanogels could effectively inhibit the formation of mucins aggregates in vitro, suggesting that the nanogel might have the potential to destroy mucin in respiratory disease. Furthermore, in the ovalbumin (OVA)/NTHi-induced Balb/c mice model of neutrophilic asthma, the number of neutrophils in the alveolar lavage fluid and the percentage of inflammatory cells in the blood were effectively reduced by exposure to tower nebulized administration of ECAT nanogels, and reversing airway hyperresponsiveness (AHR) and reducing inflammation in neutrophilic asthma mice. In conclusion, the construction of ECAT nanogels was a feasible anti-infective and anti-inflammatory therapeutic strategy, which demonstrated strong potential in the clinical treatment of neutrophilic asthma., (Copyright © 2024. Published by Elsevier B.V.)

The development of functional nanoplatforms to improve the chemotherapy outcome and inhibit distal cancer cell metastasis remains an extreme challenge in cancer management. In this work, a human-derived PC-3 cancer cell membrane-camouflaged chitosan-polypyrrole nanogel (CH-PPy NG) platform, which can be loaded with chemotherapeutic drug docetaxel (DTX) and RANK siRNA for targeted chemotherapy and gene silencing-mediated metastasis inhibition of late-stage prostate cancer in a mouse model, is reported. The prepared NGs with a size of 155.8 nm show good biocompatibility, pH-responsive drug release profile, and homologous targeting specificity to cancer cells, allowing for efficient and precise drug/gene co-delivery. Through in-vivo antitumor treatment in a xenografted PC-3 mouse tumor model, it is shown that such a CH-PPy NG-facilitated co-delivery system allows for effective chemotherapy to slow down the tumor growth rate, and effectively inhibits the metastasis of prostate cancer to the bone via downregulation of the RANK/RANKL signaling pathway. The created CH-Ppy NGs may be utilized as a promising platform for enhanced chemotherapy and anti-metastasis treatment of prostate cancer., (© 2024 Wiley‐VCH GmbH.)

The objective of this study is to create a nanoemulgel formulation of Ribociclib (RIBO), a highly selective inhibitor of CDK4/6 through the utilization of spontaneous emulsification method. An experimental investigation was conducted to construct pseudo-ternary phase diagram for the most favourable formulation utilizing rice bran oil, which is known for its diverse anticancer properties. The formulation consisted of varying combination of the surfactant and as the co-surfactant (Tween 80 and Transcutol, respectively) referred to as Smix and the trials were optimized to get the desired outcome. The nanoemulsion (NE) formulations that were developed exhibited a droplet size of 179.39 nm, accompanied with a PDI of 0.211. According to the data released by Opt-RIBO-NE, it can be inferred that the Higuchi model had the most favourable fit among many kinetics models considered. The results indicate that the use of nanogel preparations for the topical delivery of RIBO in breast cancer therapy, specifically RIBO-NE-G, is viable. This is supported by the extended release of the RIBO, and the appropriate level of drug permeation observed in Opt-RIBO-NE-G. Due to RIBO and Rice Bran oil, RIBO-NE-G had greater antioxidant activity, indicating its effectiveness as antioxidants. The stability of the RIBO-NE-G was observed over a period of three months, indicating a favourable shelf life. Therefore, this study proposes the utilization of an optimized formulation of RIBO-NE-G may enhance the efficacy of anticancer treatment and mitigate the occurrence of systemic side effects in breast cancer patients, as compared to the use of suspension preparation of RIBO.

While long-acting injectable treatments are gaining increasing interest in managing chronic diseases, the available drug delivery systems almost exclusively rely on hydrophobic matrixes, limiting their application to either hydrophobic drugs or large and hydrophilic molecules such as peptides. To address the technological lock for long-acting delivery systems tailored to small, hydrophilic drugs such as anticancer and antiviral nucleoside/nucleotide analogues, we have synthesized and characterized an original approach with a multi-scale structure: (i) a nucleotide (adenosine triphosphate, ATP) is first incorporated in hydrophilic chitosan-Fe(III) nanogels; (ii) these nanogels are then transferred by freeze-drying and resuspension into a water-free, hydrophobic medium containing PLGA and an organic solvent, N-methyl-2-pyrrolidone. We show that this specific association allows an injectable and homogeneous dispersion, able to form in situ implants upon injection in physiological or aqueous environments. This system releases ATP in vitro without any burst effect in a two-step mechanism, first as nanogels acting as an intermediate reservoir over a week, then as free drug over several weeks. In vivo studies confirmed the potential of such nanostructured implants for sustained drug release following subcutaneous injection to mice hock, opening perspectives for sustained and targeted delivery through the lymphatic system., (© 2024. Controlled Release Society.)

Nano-delivery systems hold great promise for the treatment of rheumatoid arthritis (RA). Current research efforts are primarily focused on enhancing their targeting capabilities and efficacy. Here, this study proposes a novel viral-mimicking ternary polyplexes system for the controlled delivery of the anti-inflammatory drug Cyclosporin A (CsA) to effectively treat RA. The ternary polyplexes consist of a nanogel core loaded with CsA and a hyaluronic acid shell, which facilitates CD44-mediated targeting. By mimicking the Trojan Horse strategy employed by viruses, these polyplexes undergo a stepwise process of deshielding and disintegration within the inflamed joints. This process leads to the release of CsA within the cells and the scavenging of pathogenic factors. This study demonstrates that these viral-mimicking ternary polyplexes exhibit rapid targeting, high accumulation, and prolonged persistence in the joints of RA mice. As a result, they effectively reduce inflammation and alleviate symptoms. These results highlight the potential of viral-mimicking ternary polyplexes as a promising therapeutic approach for the targeted and programmed delivery of drugs to treat not only RA but also other autoimmune diseases., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Antitumor agents often lack effective penetration and accumulation to achieve high therapeutic efficacy in treating solid tumors. Nanomotor-based nanomaterials offer a potential solution to address this obstacle. Among them, nitric oxide (NO) based nanomotors have garnered attention for their potential applications in nanomedicine. However, there widespread clinical adoption has been hindered by their complex preparation processes. To address this limitation, we have developed a NO-driven nanomotor utilizing a convenient and scalable nanogel preparation procedure. These nanomotors, loaded with the fluorescent probe / sonosensitizer chlorin e6 (Ce6), were specifically engineered for sonodynamic therapy. Through comprehensive in vitro investigations using both 2D and 3D cell models, as well as in vivo analysis of Ce6 fluorescent signal distribution in solid tumor models, we observed that the self-propulsion of these nanomotors significantly enhances cellular uptake and tumor penetration, particularly in solid tumors. This phenomenon enables efficient access to challenging tumor regions and, in some cases, results in complete tumor coverage. Notably, our nanomotors have demonstrated long-term in vivo biosafety. This study presents an effective approach to enhancing drug penetration and improving therapeutic efficacy in tumor treatment, with potential clinical relevance for future applications., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive impairment and memory loss. In this study, AD was experimentally induced in rats using aluminum chloride (AlCl 3 ) and D-galactose (D-gal). Fisetin (Fis), a natural compound with antioxidant and anti-inflammatory properties, has potential for neurodegeneration management, but its low bioavailability limits clinical applications. To address this, we synthesized and characterized Pluronic-2-Acrylamido-2-methylpropane sulfonic acid (PLUR-PAMPS) nanogels using gamma radiation and successfully loaded Fis onto them (Fis-PLUR-PAMPS). The optimal formulation exhibited minimal particle size, a highly acceptable polydispersity index, and the highest zeta-potential, enhancing stability and solubilization efficiency. Our goal was to improve Fis's bioavailability and assess its efficacy against AlCl 3 /D-gal-induced AD. Male albino Wistar rats were pre-treated orally with Fis (40 mg/kg) or Fis-PLUR-PAMPS for seven days, followed by a seven-day intraperitoneal injection of AlCl 3 and D-gal. Behavioral assessments, histopathological analysis, and biochemical evaluation of markers related to AD pathology were conducted. Results demonstrated that Fis-PLUR-PAMPS effectively mitigated cognitive impairments and neurodegenerative signs induced by AlCl 3 /D-gal. These findings suggest that Fis-PLUR-PAMPS nanogels enhance Fis's bioavailability and therapeutic efficacy, offering a promising approach for AD management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This research describes the eco-friendly green synthesis of silver nanoparticles employing Pongamia pinnata seed extracts loaded with nanogel formulations (AgNPs CUD NG) to improve the retention, accumulation, and the penetration of AgNPs into the epidermal layer of psoriasis. AgNPs were synthesized using the Box-Behnken design. Optimized AgNPs and AgNPs CUD NG were physico-chemically evaluated using UV-vis spectroscopy, SEM, FT-IR, PXRD, viscosity, spreadability, and retention studies. It was also functionally assessed using an imiquimod-induced rat model. The entrapment efficiency of AgNPs revealed ~ 79.35%. Physico-chemical parameters announced the formation of AgNPs via surface plasmon resonance and interaction between O-H, C = O, and amide I carbonyl group of protein extract and AgNO 3 . Optimized AgNPs showed spherical NPs ~ 116 nm with better physical stability and suitability for transdermal applications. AgNPs CUD NG revealed non-Newtonian, higher spreadability, and better extrudability, indicating its suitability for a transdermal route. AgNPs CUD NG enhanced the retention of AgNPs on the psoriatic skin compared to normal skin. Optimized formulations exhibit no irritation by the end of 72 h, indicating formulation safety. AgNPs CUD NG at a dose of 1 FTU showed significant recovery from psoriasis with a PASI score of ~ 0.8 compared to NG base and marketed formulations. Results indicated that seed extract-assisted AgNPs in association with CUD-based NG formulations could be a promising nanocarrier for psoriasis and other skin disorders., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Thermoresponsive nanogels (tNGs) are promising candidates for dermal drug delivery. However, poor incorporation of hydrophobic drugs into hydrophilic tNGs limits the therapeutic efficiency. To address this challenge, β-cyclodextrins (β-CD) are functionalized by hyperbranched polyglycerol serving as crosslinkers (hPG-βCD) to fabricate βCD-tNGs. This novel construct exhibits augmented encapsulation of hydrophobic drugs, shows the appropriate thermal response to dermal administration, and enhances the dermal penetration of payloads. The structural influences on the encapsulation capacity of βCD-tNGs for hydrophobic drugs are analyzed, while concurrently retaining their efficacy as skin penetration enhancers. Various synthetic parameters are considered, encompassing the acrylation degree and molecular weight of hPG-βCD, as well as the monomer composition of βCD-tNGs. The outcome reveals that βCD-tNGs substantially enhance the aqueous solubility of Nile Red elevating to 120 µg mL -1 and augmenting its dermal penetration up to 3.33 µg cm -2 . Notably, the acrylation degree of hPG-βCD plays a significant role in dermal drug penetration, primarily attributed to the impact on the rigidity and hydrophilicity of βCD-tNGs. Taken together, the introduction of the functionalized β-CD as the crosslinker in tNGs presents a novel avenue to enhance the efficacy of hydrophobic drugs in dermatological applications, thereby offering promising opportunities for boosted therapeutic outcomes., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)

Dexamethasone (DEX) has been demonstrated to inhibit the inflammatory corneal neovascularization (CNV). However, the therapeutic efficacy of DEX is limited by the poor bioavailability of conventional eye drops and the increased risk of hormonal glaucoma and cataract associated with prolonged and frequent usage. To address these limitations, we have developed a novel DEX-loaded, reactive oxygen species (ROS)-responsive, controlled-release nanogel, termed DEX@INHANGs. This advanced nanogel system is constructed by the formation of supramolecular host-guest complexes by cyclodextrin (CD) and adamantane (ADA) as a cross-linking force. The introduction of the ROS-responsive material, thioketal (TK), ensures the controlled release of DEX in response to oxidative stress, a characteristic of CNV. Furthermore, the nanogel's prolonged retention on the corneal surface for over 8 h is achieved through covalent binding of the integrin β1 fusion protein, which enhances its bioavailability. Cytotoxicity assays demonstrated that DEX@INHANGs was not notably toxic to human corneal epithelial cells (HCECs). Furthermore, DEX@INHANGs has been demonstrated to effectively inhibit angiogenesis in vitro. In a rabbit model with chemically burned eyes, the once-daily topical application of DEX@INHANGs was observed to effectively suppress CNV. These results collectively indicate that the nanomedicine formulation of DEX@INHANGs may offer a promising treatment option for CNV, offering significant advantages such as reduced dosing frequency and enhanced patient compliance., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In recent years, there has been a growing interest in multifunctional theranostic agents capable of delivering therapeutic payloads while facilitating simultaneous diagnostic imaging of diseased sites. This approach offers a comprehensive strategy particularly valuable in dynamically evolving diseases like cancer, where combining therapy and diagnostics provides crucial insights for treatment planning. Nanoscale platforms, specifically nanogels, have emerged as promising candidates due to their stability, tunability, and multifunctionality as carriers. As a well-studied subgroup of soft polymeric nanoparticles, nanogels exhibit inherent advantages due to their size and chemical compositions, allowing for passive and active targeting of diseased tissues. Moreover, nanogels loaded with therapeutic and diagnostic agents can be designed to respond to specific stimuli at the disease site, enhancing their efficacy and specificity. This capability enables fine-tuning of theranostic platforms, garnering significant clinical interest as they can be tailored for personalized treatments. The ability to monitor tumor progression in response to treatment facilitates the adaptation of therapies according to individual patient responses, highlighting the importance of designing theranostic platforms to guide clinicians in making informed treatment decisions. Consequently, the integration of therapy and diagnostics using theranostic platforms continues to advance, offering intelligent solutions to address the challenges of complex diseases such as cancer. In this context, nanogels capable of delivering therapeutic payloads and simultaneously armed with diagnostic modalities have emerged as an attractive theranostic platform. This review focuses on advances made toward the fabrication and utilization of theranostic nanogels by highlighting examples from recent literature where their performances through a combination of therapeutic agents and imaging methods have been evaluated.

Nanogels are aqueous dispersions of hydrogel particles formed by physically or chemically cross-linked polymer networks of nanoscale size. Herein, we devised a straightforward technique to fabricate a novel class of physically cross-linked nanogels via a self-assembly process in water involving α-cyclodextrin and a mannose molecule that was hydrophobically modified using an alkyl chain. The alkyl chain-modified mannose was synthesized in five steps, starting with D-mannose. Subsequently, nanogels were formed by subjecting α-cyclodextrin and the hydrophobically modified mannose to magnetic stirring in water. By adjusting the mole ratio between the hydrophobically modified mannose and α-cyclodextrin, nanogels with an average 100-150 nm diameter were obtained. Physicochemical and structural analyses by 1 H NMR and X-ray diffraction unveiled a supramolecular and hierarchical mechanism underlying the creation of these nanogels. The proposed mechanism of nanogel formation involves two distinct steps: initial interaction of hydrophobically modified mannose with α-cyclodextrin resulting in the formation of inclusion complexes, followed by supramolecular interactions among these complexes, ultimately leading to nanogel formation after 72 h of stirring. We demonstrated the nanogels' ability to encapsulate a short peptide ([p- t BuF 2 , R 5 ]SHf) as a water-soluble drug model. This discovery holds promise for potentially utilizing these nanogels in drug delivery applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The goal of this study was to formulate tacrolimus nanogel based on nanostructured lipid carrier (NLC) in order to improve the efficacy, aesthetic, and patient compliance for the treatment of psoriasis. The microemulsion method was used to create phase diagrams and NLCs were prepared using points obtained from the microemulsion region and characterized. The gelling agent carbopol was used to develop an NLC-based nanogel. The pH, drug assay, viscosity, spreadability, and in vitro release of the nanogel, were evaluated. Ex vivo cytotoxicity of the formulation was assessed in murine fibroblast cells. Oxazolone and imiquimod models of psoriasis were used to assess the effectiveness of the nanogel. The NLCs exhibited a submicron particle size of 320 ± 10 nm, a low polydispersity index (<0.3), and a zeta potential of -19.4 mV. Morphological analysis revealed spherical nanoparticles with an encapsulation efficiency of 60 ± 3 %. The nanogel maintained a pH of 6.0 ± 0.5 and possessed a remarkable drug content of 99.73 ± 1.4 %. It exhibited pseudoplastic flow behaviour, ensuring easy spreadability, and demonstrated sustained drug release exceeding 90 % over a 24-hr period. Ex vivo cytotoxicity assessments revealed that the nanogel was safe because no cell death was induced. Nanogel resolved psoriatic blisters, was non-irritating and improved skin elasticity. The favorable properties, safety profile, and remarkable efficacy show the potential of the nanogel as a patient-friendly and effective therapeutic option for psoriasis treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)