Currently, research in nanoparticles as a drug delivery system has broadened to include their use as a delivery system for bioactive substances and a diagnostic or theranostic system. Nanogels, nanoparticles containing a high amount of water, have gained attention due to their advantages of colloidal stability, core-shell structure, and adjustable structural components. These advantages provide the potential to design and fabricate multifunctional nanosystems for various biomedical applications. Modified or functionalized polymers and some metals are components that markedly enhance the features of the nanogels, such as tunable amphiphilicity, biocompatibility, stimuli-responsiveness, or sensing moieties, leading to specificity, stability, and tracking abilities. Here, we review the diverse designs of core-shell structure nanogels along with studies on the fabrication and demonstration of the responsiveness of nanogels to different stimuli, temperature, pH, reductive environment, or radiation. Furthermore, additional biomedical applications are presented to illustrate the versatility of the nanogels.

Silk fibroin (SF) hydrogels can be obtained via self-assembly, but this process takes several days or weeks, being unfeasible to produce cell carrier hydrogels. In this work, a phospholipid, namely, 1,2-dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol) sodium salt (DMPG), was used to induce and accelerate the gelation process of SF solutions. Due to the amphipathic nature and negative charge of DMPG, electrostatic and hydrophobic interactions between the phospholipids and SF chains will occur, inducing the structural transition of SF chains to the beta sheet and consequently a rapid gel formation is observed (less than 50 min). Moreover, the gelation time can be controlled by varying the lipid concentration. To assess the potential of the hydrogels as cell carriers, several mammalian cell lines, including L929, NIH/3T3, SaOS-2, and CaSki, were encapsulated into the hydrogel. The silk-based hydrogels supported the normal growth of fibroblasts, corroborating their cytocompatibility.Interestingly, an inhibition in the growth of cancer-derived cell lines was observed.Therefore, DMPG-induced SF hydrogels can be successfully used as a 3D platform for in situ cell encapsulation, opening promising opportunities in biomedical applications, such as in cell therapies and tissue regeneration.Bombyx mori "Nangnoi Srisaket 1" Thai silk cocoons were obtained from Queen Sirikit Sericulture Center, Srisaket province, Thailand.DMPG and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) were purchased from Avanti Lipids Polar, USA. Cell culture medium and all other reagents were purchased from Thermo Fisher Scientific.All reagents were of analytical grade. | SF solution preparation and its zeta potential determinationSF solution was prepared using the method adapted from Kim, Park, Joo Kim, Wada, and Kaplan (2005). In brief, silk cocoons were boiled in 0.02 M Na 2 CO 3 for 20 min, followed by their thoroughly washing with distilled water. The extracted silk fibre was then dissolved in 9.3 M LiBr at 60°C for 4 hr. The silk solution was dialysed against distilled water using a dialysis tube (MWCO 12-16 kDa; Sekisui, Japan) for 48 hr. The final concentration was approximately 6%, which was determined from dried solid weight.Analysis of zeta potential of the SF solution was conducted using laser doppler electrophoresis in a Zetasizer Nano ZS equipment (Malvern Instruments) at 25°C.

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Accelerating the gelation of silk fibroin (SF) solution from several days or weeks to minutes or few hours is critical for several applications (e.g., cell encapsulation, bio-ink for 3D printing, and injectable controlled release). In this study, the rapid gelation of SF induced by a gold salt (Au3+) as well as the cytocompatibility of Au3+-mediated SF hydrogels are reported. The gelation behaviors and mechanisms of regenerated SF and thiolated SF (tSF) were compared. Hydrogels can be obtained immediately after mixing or within three days depending on the types of silk proteins used and amount of Au3+. Au3+-mediated SF and tSF hydrogels showed different color appearances. The color of Au-SF hydrogels was purple-red, whereas the Au-tSF hydrogels maintained their initial solution color, indicating different gelation mechanisms. The reduction of Au3+ by amino groups and further reduction to Au by tyrosine present in SF, resulting in a dityrosine bonding and Au nanoparticles (NPs) production, are proposed as underlying mechanisms of Au-SF gel formation. Thiol groups of the tSF reduced Au3+ to Au+ and formed a disulfide bond, before a formation of Au+-S bonds. Protons generated during the reactions between Au3+ and SF or tSF led to a decrease of the local pH, which affected the chain aggregation of the SF, and induced the conformational transition of SF protein to beta sheet. The cytocompatibility of the Au-SF and tSF hydrogels was demonstrated by culturing with a L929 cell line, indicating that the developed hydrogels can be promising 3D matrices for different biomedical applications.