## 1 Introduction  
Protein drugs with uncontrolled dosage can usually cause severe side effects such as the incidence of complications in normal tissues and organs, despite their outstanding treating function in different types of human diseases [1]. To date, the localized and controlled release of protein drugs has been achieved in many research studies. In the drug and gene release systems, hydrogels were widely used as stimuli-responsive materials because of their responsiveness to external stimuli such as light, temperature, pH, metal ions, or other molecules [2; 3; 4; 5]. However, the big obstacle of hydrogel as a drug release carrier is the fast and burst release of drugs due to its high permeability, which would give rise to adverse influence in vivo [6]. Therefore, hydrogel functionalization has been extensively studied to improve the effectiveness of its sustained release. The incorporation of different affinity ligands such as metal ion chelating ligands [7], heparin or heparan sulfate [8; 9; 10], and streptavidin or biotin [11] into hydrogels have been widely used to improve the affinity of hydrogels with protein drugs and overcome burst release. For instance, [PERSON] et al. have designed a heparin-based system to immobilize neurotrophin-3 in the fibrin gel by non-covalent interaction to rein in the diffusion-based release of neurothrombin-3 [9]. In addition, the combination of DNA with some nanostructures has also been getting a lot of attention [12; 13; 14; 15; 16; 17; 18]. Although those molecules can be used as a connector for many biologics, many problems still exist, such as low specificity, low affinity, and high toxicity. In recent decades, oligonucleotide aptamers, which are selected from DNA/RNA libraries by Systematic Evolution of Ligands by Exponential Enrichment (SELEX), have been proven to have the capacity to recognize any class of target molecules with high affinity and specificity [19]. Moreover, unlike other affinity ligands, aptamer can be hybridized with complementary sequences (CSs). Therefore, the reasonable design of CSs can adjust aptamer's binding function, and induce the rapid dissociation of protein-aptamer complexes [20; 21; 22; 23]. Hence, aptamers were usually incorporated into hydrogels as affinity ligands to expand the application of hydrogels in the field of controlled drug delivery [24; 25; 26]. For instance, a sustained-release polyacrylamide (PAA) hydrogel system was achieved through using platelet-derived growth factor-BB aptamer to reserve the protein drugs [20]. As reported in recent literatures, most aptamers were usually functionalized into synthetic polymeric hydrogels such as PAA or polyethylene glycol methacrylate (PEGMA) by radical polymerization [24; 27; 28; 29]. The strict demands of the modified process for aptamer\(-\)polymer hybrids and the toxicity of all kinds of initiators limit their application in vivo in the biomedical fields. For instance, a hydrogel system that can release proteins via sequential photoreaction and hybridization in a self-programming manner has been reported recently [30]. This hydrogel system may be tuned to control the release of other fragile bioactive substances such as vaccines, viruses, or cells. However, the complicated and tedious synthesis steps of a photolabile linker, photoresponsive DNA, and hydrogel limit their application. In our previous work, in order to simplify the modification steps and control the spatial distribution of aptamers in hydrogel, an anti-thrombin aptamer was functionalized into polyethylene glycol (PEG) hydrogel via UV light-induced thiol-ene click chemistry [31], but the UV light may potential damage the cells or tissues. In this work, we designed an aptamer-functionalized DNA hydrogel as the controlled protein release carrier to solve the above problems. The three-dimensional DNA hydrogels were cross-linked by the one-pot self-assembly of two kinds of DNA building blocks (X-shaped and L-shaped DNA units) and a single-stranded DNA aptamer (S-DNA) via the hybridization of the respective \"sticky ends\".