DNA hydrogels have attracted increasing attention owing to their excellent permeability and high mechanical strength, together with thixotropy, versatile programmability and good biocompatibility. However, the moderate biostability and immune stimulation of DNA have arisen as big concerns for future potential clinical applications. Herein, we report the self-assembly of a novel L-DNA hydrogel, which inherited the extraordinary physical properties of a D-DNA hydrogel. With the mirror-isomer deoxyribose, this hydrogel exhibited improved biostability, withstanding fetal bovine serum (FBS) for at least 1 month without evident decay of its mechanical properties. The low inflammatory response of the L-DNA hydrogel has been verified both in vitro and in vivo. Hence, this L-DNA hydrogel with outstanding biostability and biocompatibility can be anticipated to serve as an ideal 3D cell-culture matrix and implanted bio-scaffold for long-term biomedical applications.Hydrogels possess similar molecular networks and exhibit comparable physical properties to the natural extracellular matrix (ECM), and have therefore provided an ideal platform for three-dimensional (3D) cell culture and tissue engineering. [1] Among them, DNA hydrogels have attracted much attention owing to their unique properties, including excellent permeability and high mechanical strength, together with thixotropy, versatile programmability and good biocompatibility, [2] which have promoted their application in cell manipulation, [3] targeted therapy, [4] 3D bio-printing, [5] drug delivery, [6] and tissue regeneration. [7] In previous studies, DNA hydrogels have been demonstrated with good cytocompatibility in vitro. However, some concerns on their inflammation in vivo arose recently, because some DNA components and their degradation fragments are reported to lead to the stimulation of immune responses, [8] for example, CpG as a vaccine adjuvant. [9] While many efforts have been made to decrease the immune responses [8b, 10] of DNA materials, quick hydrolysis of DNA under physiological conditions is still another challenge for their long-term application. [11] Therefore, there is an urgent need to reduce

Osteoarthritis (OA) is a musculoskeletal disorder affecting ∼500 million people worldwide. Metformin (MET), as an oral hypoglycemic drug approved by the Food and Drug Administration, has displayed promising potential for treating OA. Nonetheless, in the articular cavity, MET suffers from rapid clearance and cannot circumvent the severe inflammatory environment, greatly confining the therapeutic efficacy. Herein, DNA supramolecular hydrogel (DSH) has been utilized as a sustained drug delivery vehicle for MET to treat OA, which dramatically prolonged the retention time of MET in the articular cavity from 3 to 14 days and simultaneously exerted a greater anti-inflammatory effect. Our delivery platform, termed MET@DSH, better protects cartilage than single-agent MET. Additionally, the corresponding molecular mechanisms underlying the therapeutic effects were also analyzed. We anticipate this DNA supramolecular hydrogel-enabled sustained drug delivery and anti-inflammatory strategy will reshape the current landscape of OA treatment.

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DNA hydrogels have attracted increasing attention owing to their excellent permeability and high mechanical strength, together with thixotropy, versatile programmability and good biocompatibility. However, the moderate biostability and immune stimulation of DNA have arisen as big concerns for future potential clinical applications. Herein, we report the self‐assembly of a novel l‐DNA hydrogel, which inherited the extraordinary physical properties of a d‐DNA hydrogel. With the mirror‐isomer deoxyribose, this hydrogel exhibited improved biostability, withstanding fetal bovine serum (FBS) for at least 1 month without evident decay of its mechanical properties. The low inflammatory response of the l‐DNA hydrogel has been verified both in vitro and in vivo. Hence, this l‐DNA hydrogel with outstanding biostability and biocompatibility can be anticipated to serve as an ideal 3D cell‐culture matrix and implanted bio‐scaffold for long‐term biomedical applications.