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In addition to oxidative stress and impaired angiogenesis, the overexpression of metalloproteinases (MMPs) and proinflammatory cytokines, which are promoted by hyperglycemia, causes chronic inflammation in diabetic wounds. Herein, TA‐siRNA nanogels are prepared for the first time on the basis of the self‐assembling interaction between tannic acid (TA) and short interfering RNA (siRNA). The efficient, biodegradable nanogels are cross‐linked with poly(vinyl alcohol) (PVA), human‐like collagen (HLC), TA, and borax to prepare adaptive, conductive PHTB (TA‐siRNA) hydrogels. In response to high levels of reactive oxygen species (ROS), the ROS‐responsive borate ester bonds in the hydrogels are oxidized and broken, and TA‐siRNA nanogels are released into cells to reduce the expression of the MMP‐9. Moreover, the TA and HLC promote collagen expression, reduce inflammation, and ROS level. It is found that electrical stimulation (ES) promotes the in vivo release of TA‐siRNA nanogels from PHTB (TA‐siRNA) hydrogels and endocytosis of the nanogels. The combination therapy using ES and PHTB (TA‐siRNA) hydrogels accelerates the healing of diabetic wounds by reducing the levels of ROS and MMP‐9 and promoting the polarization of macrophages, production of collagen, and angiogenesis. This study provides insights on the design of functional gene‐delivery and efficient therapeutic strategies to promote the repair of diabetic chronic wounds. The efficient, nontoxic, biodegradable self‐assembled tannic acid‐short interfering RNA (TA‐siRNA) nanogels could promote the effective cellular internalization of siRNA to reduce the expression of the target gene. Adaptive conductive hydrogels combined with electrical stimulation (ES) could promote the repair of diabetic chronic wounds by scavenging reactive oxygen species (ROS), metalloproteinases‐9 (MMP‐9), and proinflammatory factors and promoting macrophage polarization and vascularization.

Due to their increased surface area, extent of swelling and active substance-loading capacity and flexibility, nanogels made from natural and synthetic polymers have gained significant interest in scientific and industrial areas. In particular, the customized design and implementation of nontoxic, biocompatible, and biodegradable micro/nano carriers makes their usage very feasible for a range of biomedical applications, including drug delivery, tissue engineering, and bioimaging. The design and application methodologies of nanogels are outlined in this review. Additionally, the most recent advancements in nanogel biomedical applications are discussed, with particular emphasis on applications for the delivery of drugs and biomolecules.

Development of nanosystems that can be integrated with macrophages (MAs), an emerging carrier system, for effective tumor therapy remains to be challenging. We report here the development of MAs specifically loaded with hyaluronic acid (HA) nanogels (NGs) encapsulated with a photothermal agent of polypyrrole (PPy) and anticancer drug doxorubicin (DOX) (HA/DOX@PPy NGs) for tumor homing and combination photothermo-chemotherapy. Cystamine dihydrochloride-crosslinked HA NGs were first prepared through a double emulsification method, then loaded with PPy via an oxidization polymerization and physically encapsulated with DOX. The created HA/DOX@PPy NGs were well characterized and subjected to be endocytosed by MAs (MAs-NGs). The MAs-mediated tumor-homing property, phenotype changes and photothermal performance of MAs-NGs were investigated , and a subcutaneous tumor model was also established to confirm their targeting capability and enhanced antitumor therapy effect . The generated hybrid NGs possess a size around 77 nm and good colloidal stability, and can be specifically endocytosed by MAs without appreciably affecting their normal biofunctionalities. In particular, NG-loaded MAs display excellent cancer cell and tumor homing property. Systemic administration of the MAs-NGs leads to the significant inhibition of a subcutaneous tumor model through combination photothermo-chemotherapy under laser irradiation. The developed hybrid HA-based NG nanosystem incorporated with PPy and DOX fully integrates the coordination and heating property of PPy to regulate the optimized DOX release in the tumor region with the assistance of MA-mediated tumor homing, providing a promising cell therapy strategy for enhanced antitumor therapy.

Nanogels are being explored as drug delivery agents for targeting cancer due to their easy tailoring properties and ability to efficiently encapsulate therapeutics of diverse nature through simple mechanisms. Nanogels are proficiently internalized by the target cells, avoid accumulating in nontarget tissues thereby lower the therapeutic dosage and minimize harmful side effects. However, there is an urgent need for relevant clinical data from nanogels so as to allow translation of the nanogel concept into a viable therapeutic application for the treatment of cancer. This review highlights some of the recent progress in nanogels as a carrier in the field of nanomedicine for the treatment of cancer. The present review critically analyzes the use of extracellular pH targeting for nanogels, siRNA delivery, PEGylated nanogels, multi-responsive nanogels and intracellular delivery of nanogels for improved therapy of cancer.

Recently, nanogels have been identified as innovative formulations for enlarging the application of hydrogels (HGs) in the area of drug delivery or in diagnostic imaging. Nanogels are HGs-based aggregates with sizes in the range of nanometers and formulated in order to obtain injectable preparations. Regardless of the advantages offered by peptides in a hydrogel preparation, until now, only a few examples of peptide-based nanogels (PBNs) have been developed. Here, we describe the preparation of stable PBNs based on Fmoc-Phe-Phe-OH using three different methods, namely water/oil emulsion (W/O), top-down, and nanogelling in water. The effect of the hydrophilic–lipophilic balance (HLB) in the formulation was also evaluated in terms of size and stability. The resulting nanogels were found to encapsulate the anticancer drug doxorubicin, chosen as the model drug, with a drug loading comparable with those of the liposomes.

Nanogels are polymer-based, crosslinked hydrogel particles on the nanometer scale. Nanogels developed from synthetic and natural polymers have gathered a great deal of attention in industry and scientific society due to having an increased surface area, softness, flexibility, absorption, and drug loading ability, as well as their mimicking the environment of a tissue. Nanogels having biocompatibility, nontoxic and biodegradable properties with exceptional design, fabrication, and coating facilities may be used for a variety of different biomedical applications, such as drug delivery and therapy, tissue engineering, and bioimaging. Nanogels fabricated by chemical crosslinking and physical self-assembly displayed the ability to encapsulate therapeutics, including hydrophobic, hydrophilic, and small molecules, proteins, peptides, RNA and DNA sequences, and even ultrasmall nanoparticles within their three-dimensional polymer networks. One of the many drug delivery methods being investigated as a practical option for targeted delivery of drugs for cancer treatment is nanogels. The delivery of DNA and anticancer drugs like doxorubicin, epirubicin, and paclitaxel has been eased by polymeric nanogels. Stimuli-responsive PEGylated nanogels have been reported as smart nanomedicines for cancer diagnostics and therapy. Another promising biomedical application of nanogels is wound healing. Wounds are injuries to living tissue caused by a cut, blow, or other impact. There are numerous nanogels having different polymer compositions that have been reported to enhance the wound healing process, such as hyaluronan, poly-L-lysine, and berberine. When antimicrobial resistance is present, wound healing becomes a complicated process. Researchers are looking for novel alternative approaches, as foreign microorganisms in wounds are becoming resistant to antibiotics. Silver nanogels have been reported as a popular antimicrobial choice, as silver has been used as an antimicrobial throughout a prolonged period. Lignin-incorporated nanogels and lidocaine nanogels have also been reported as an antioxidant wound-dressing material that can aid in wound healing. In this review, we will summarize recent progress in biomedical applications for various nanogels, with a prime focus on cancer and wound healing.

Hematoxylin (HT) is a natural staining dye used in histopathology, often combined with Eosin for H&E staining. A poly(hematoxylin-co-l-lysine) (p(HT-co-l)) nanonetwork was synthesized through a one-step Mannich condensation reaction using formaldehyde as a linking agent. The resulting p(HT-co-l) nanogels had an average size of about 200 nm and exhibited a smooth surface and desirable functional groups such as -OH, -NH2, and -COOH, as recognized by FT-IR analysis. The isoelectric point (IEP) of the p(HT-co-l) nanogel was determined as pH 7.9, close to physiological environments, despite HT being acidic IEP at pH 1.7 and l-lysine being basic IPE at pH 8.7. The time-dependent swelling studies of p(HT-co-l) nanogels were carried out using dynamic light scattering (DLS) in different salt solutions, e.g., MgCl2, KNO3, KCl, PBS, and DI water environments revealed that nanogels have high swelling ability depending on the medium, e.g., >10-fold in a saline solution compared to distilled water within 1.5 h. Hydrolytic degradation studies in PBS demonstrated a linear release profile up to 125 h at 37.5 °C. The p(HT-co-l) nanogels also demonstrated significant antimicrobial and antifungal activities against E. coli (ATCC 8739), S. aureus (ATCC 6538), and C. albicans (ATCC 10231). Furthermore, biocompatibility tests indicated that p(HT-co-l) nanogels are more biocompatible than HT alone, as tested with human Nuli-1 bronchial epithelial cells.

The low response rate of current cancer immunotherapy suggests the presence of few antigen-specific T cells and a high number of immunosuppressive factors in tumor microenvironment (TME). Here, we develop a syringeable immunomodulatory multidomain nanogel (iGel) that overcomes the limitation by reprogramming of the pro-tumoral TME to antitumoral immune niches. Local and extended release of immunomodulatory drugs from iGel deplete immunosuppressive cells, while inducing immunogenic cell death and increased immunogenicity. When iGel is applied as a local postsurgical treatment, both systemic antitumor immunity and a memory T cell response are generated, and the recurrence and metastasis of tumors to lungs and other organs are significantly inhibited. Reshaping of the TME using iGel also reverts non-responding groups to checkpoint blockade therapies into responding groups. The iGel is expected as an immunotherapeutic platform that can reshape immunosuppressive TMEs and synergize cancer immunotherapy with checkpoint therapies, with minimized systemic toxicity. The limited efficacy of current immunotherapy suggests low antigen-specific T cells and immunosuppressive factors in tumor microenvironment (TME). Here, the authors develop a syringeable immunomodulatory multi-domain nanogel that can reprogram the TME and induce enhanced cancer immunotherapy.

Nanogels have high tunability and stability while being able to sense and respond to external stimuli by showing changes in the gel volume, water content, colloidal stability, mechanical strength, and other physical/chemical properties. In this article, advances in the preparation of nanogels will be reviewed. The application potential of nanogels in drug delivery will also be highlighted. It is the objective of this article to present a snapshot of the recent knowledge of nanogel preparation and application for future research in drug delivery.

Physiological barriers inside of tumor tissue often result in poor interstitial penetration and heterogeneous intratumoral distribution of nanoparticle-based drug delivery systems (DDS). Novel, matrix metalloproteinase (MMP)-sensitive peptide-crosslinked nanogels (pNGs) as multistage DDS are reported with a beneficial size reduction property to promote the process of deep tissue penetration. : The presented pNGs are based on a dendritic polyglycerol (dPG) scaffold crosslinked by a modified MMP-sensitive fluorogenic peptide. The crosslinker integrates degradability in response to proteases present in the tumor microenvironment. Surfactant-free, inverse nanoprecipitation is employed to prepare the nanogels using strain-promoted click chemistry. The size and crosslinking density of the pNGs are controlled by the functionalization degree of dPG with cyclooctyne groups and by the peptide crosslinker fraction. The intrinsic reporter moiety of the crosslinker was used to study the influence of pNG compositions on the degradation profile. The therapeutic drug Doxorubicin was conjugated through a pH-sensitive linkage to dPG to form a multistage DDS. The penetration behavior of the pNGs was studied using agarose matrix and multicellular tumor spheroids (MCTS). : Nanogel sizes were controlled in the range of 150-650 nm with narrow size distributions and varying degrees of crosslinking. The pNGs showed stability in PBS and cell media but were readily degraded in the presence of MMP-7. The crosslinking density influenced the degradation kinetic mediated by MMP-7 or cells. Stable conjugation of DOX at physiological pH and controlled drug release at acidic pH were observed. The digestions of nanogels lead to a size reduction to polymer-drug fragments which efficiently penetrated into agarose gels. Moreover, the degradable multistage pNGs demonstrated deeper penetration into MCTS as compared to their non-degradable counterparts. Thus, degradable pNGs were able to deliver their cargo and efficiently reduce the cell viability in MCTS. : The triggered size reduction of the pNGs by enzymatic degradation can facilitate the infiltration of the nanocarrier into dense tissue, and thereby promote the delivery of its cargo.