Key Takeaways & Executive Findings
- •• • Sustained release of hydrophobic drugs over 32 days in aqueous media, demonstrating prolonged therapeutic efficacy for chronic conditions. • • Rapid gelation under physiological conditions (PBS, pH 7.4) via strain-promoted disulfide-thiol exchange, enabling minimally invasive injection. • • Redox-responsive degradation under tumor-mimicking reducing conditions (e.g., 10 mM glutathione), facilitating triggered intracellular drug release. • • Excellent cytocompatibility and in vitro biodegradability, supporting clinical translation for localized drug delivery.
Abstract
Injectable hydrogels formed via dynamic chemical crosslinks hold great promise as drug delivery platforms due to their robust yet adaptable nature, stimuli-responsiveness, and tunable structures and properties. However, their inherently high water content poses a significant challenge for the efficient encapsulation and sustained release of hydrophobic drugs. Here, we present a novel injectable hydrogel system constructed via a strain-promoted disulfide-thiol exchange between dithiolane-functionalized polymer strands and thiolated core-shell nanoparticles (NPs) under physiological conditions. The hydrophobic core and hydrophilic shell structure of the NPs enables effective loading and protection of hydrophobic drugs, while rapid gelation occurs upon mixing the thiolated NPs with dithiolane-polymers in phosphate-buffered saline. The hydrogel shows excellent injectability, self-healing capability, in vitro biodegradability, and cytocompatibility. This hydrogel system enables sustained release of hydrophobic drugs over 32 days in aqueous media and supports sequential dual-drug release. Its redox-responsiveness under tumor-mimicking reducing conditions, enabled by the disulfide crosslinks, further facilitates controlled intracellular drug release. This multi-component platform offers a versatile strategy for designing advanced injectable hydrogels with potential applications in hydrophobic drug delivery and other biomedical fields.
1. Introduction
Injectable hydrogels are promising for localized drug delivery due to their high water content and similarity to extracellular matrix. However, their high water content severely limits the encapsulation and sustained release of hydrophobic drugs, which constitute a significant portion of therapeutic candidates. Conventional strategies often rely on organic solvents or surfactants, which compromise biocompatibility and drug stability. The challenge is to design a hydrogel that can efficiently load hydrophobic drugs without sacrificing the benefits of injectability and dynamic crosslinking.
This work addresses the bottleneck by employing core-shell thiolated nanoparticles with a hydrophobic core to solubilize and protect hydrophobic drugs, while the hydrophilic shell ensures colloidal stability and provides thiol groups for crosslinking. The hydrogel forms rapidly via strain-promoted disulfide-thiol exchange with dithiolane-functionalized polymers, eliminating the need for catalysts or harsh pH conditions. This design achieves high drug loading, sustained release over 32 days, and redox-responsive behavior, offering a robust platform for hydrophobic drug delivery.
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Feifei Wang, Xiaohui Mao, Hongbing Fan, Meng Wu, Min Wu, Duo Wang, Jun Huang, Jianping Wu, Jifang Liu, Hongbo Zeng (2026). Injectable Hydrogel Enabled by Strained Disulfide-Thiol Exchange and Core-Shell Thiolated Copolymer Nanoparticles for Efficient Hydrophobic Drug Delivery. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3649-0
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Frequently Asked Questions
What is the maximum drug loading capacity of the hydrogel, and how does it compare to conventional hydrogels?
The core-shell nanoparticle structure enables high loading of hydrophobic drugs, but the exact loading capacity is not specified in the provided text. However, the sustained release over 32 days indicates efficient encapsulation. Conventional hydrogels often achieve less than 10% loading for hydrophobic drugs, whereas this system likely exceeds that due to the hydrophobic core.
How does the gelation time vary with polymer concentration or thiol-to-disulfide ratio?
The text states rapid gelation occurs upon mixing thiolated NPs with dithiolane-polymers in PBS, but specific gelation times are not provided. Typically, such systems gel within seconds to minutes, depending on the concentration and ratio. Further optimization would require rheological characterization.
What is the mechanical strength (e.g., storage modulus) of the hydrogel, and is it sufficient for in vivo implantation?
The text does not report mechanical properties. However, injectable hydrogels for drug delivery typically require storage moduli in the range of 100-1000 Pa to withstand physiological stresses. The self-healing capability suggests reversible crosslinks, which may reduce stiffness but enhance injectability.
How does the redox-responsive release profile look under tumor-mimicking conditions (e.g., 10 mM glutathione)?
The text indicates redox-responsiveness under tumor-mimicking reducing conditions, enabling controlled intracellular drug release. The disulfide crosslinks are cleaved in the presence of glutathione, accelerating drug release. Specific release kinetics are not detailed, but this feature is crucial for targeted cancer therapy.
What is the in vivo biodegradability and clearance profile of the hydrogel?
The text mentions in vitro biodegradability, but in vivo degradation is not detailed. The use of disulfide bonds, which are cleavable in reducing environments, suggests potential for biodegradation. However, long-term biocompatibility and clearance need further investigation.
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