The sequential injection of hyaluronic acid–tyramine conjugates and enzymes forms biodegradable hydrogels in vivo by enzyme-induced oxidative coupling, offering high potential as a promising biomaterial for drug delivery and tissue engineering.

A green tea-based drug carrier offers a delivery system where both the drug and carrier possess therapeutic effects. When designing drug carriers, the drug-to-carrier ratio is an important consideration, because the use of high quantities of carriers can result in toxicity as a consequence of poor metabolism and elimination of the carriers1. However, these issues would be of less concern if both the drug and carrier had therapeutic effects. (−)-Epigallocatechin-3-O-gallate (EGCG), a major ingredient of green tea, has been shown, for example, to possess anticancer effects2,3,4,5,6,7, anti-HIV effects8, neuroprotective effects9 and DNA-protective effects10. Here, we show that sequential self-assembly of the EGCG derivative with anticancer proteins leads to the formation of stable micellar nanocomplexes, which have greater anticancer effects in vitro and in vivo than the free protein. The micellar nanocomplex is obtained by complexation of oligomerized EGCG with the anticancer protein Herceptin to form the core, followed by complexation of poly(ethylene glycol)–EGCG to form the shell. When injected into mice, the Herceptin-loaded micellar nanocomplex demonstrates better tumour selectivity and growth reduction, as well as longer blood half-life, than free Herceptin.

In this study, we propose an enzymatically crosslinked hyaluronic acid (HA) hydrogel with tunable mechanical strength and gelation rate as a novel injectable system. The hydrogel composed of HA–tyramine conjugate (HA–Tyr) was formed using the oxidative coupling of tyramine moieties catalyzed by hydrogen peroxide (H₂O₂) and horseradish peroxidase (HRP). The mechanical strength of the HA–Tyr hydrogel was tuned solely by the H₂O₂ amount without affecting the gelation rate. The hydrogels formed more rapidly with increasing HRP concentration and the gelation time ranged from 1 s to 20 min. A faster gelling system yielded more localized gel formation than a slower gelling one at the site where it was administered through subcutaneous injection. Studies on the swelling ratio and scanning electron microscopy images of the hydrogel structure further demonstrated that the crosslinking density was controlled by the concentration of H₂O₂ used. The mechanical strength of HA–Tyr hydrogels strongly affected the degradation rate in the presence of hyaluronidase in vitro; hydrogels degraded more slowly with increasing mechanical strength of the hydrogel. The independently tunable mechanical strength and gelation rate achieved by this enzymatically formed HA–Tyr hydrogel system will provide great advantages to a wide range of applications of injectable hydrogels, such as drug delivery and tissue regeneration.

Over the past decades, injectable hydrogels have emerged as promising biomaterials because of their biocompatibility, excellent permeability, minimal invasion, and easy integration into surgical procedures. These systems provide an effective and convenient way to administer a wide variety of bioactive agents such as proteins, genes, and even living cells. Additionally, they can be designed to be degradable and eventually cleared from the body after completing their missions. Given their unique characteristics, injectable biodegradable hydrogels have been actively explored as drug reservoir systems for sustained release of bioactive agents and temporary extracellular matrices for tissue engineering. This review provides an overview of state-of-the-art strategies towards constructing a rational design of injectable biodegradable hydrogels for protein drug delivery and tissue engineering. We also discuss the use of injectable hydrogels for gene delivery systems and biomedical adhesives.