The assembly of oligopeptide and polypeptide molecules can reconstruct various ordered advanced structures through intermolecular interactions to achieve protein-like biofunction. Here, we develop a “molecular velcro”-inspired peptide and gelatin co-assembly strategy, in which amphiphilic supramolecular tripeptides are attached to the molecular chain of gelatin methacryloyl via intra-/intermolecular interactions. We perform molecular docking and dynamics simulations to demonstrate the feasibility of this strategy and reveal the advanced structural transition of the co-assembled hydrogel, which brings more ordered β-sheet content and 10-fold or more compressive strength improvement. We conduct transcriptome analysis to reveal the role of co-assembled hydrogel in promoting cell proliferation and chondrogenic differentiation. Subcutaneous implantation evaluation confirms considerably reduced inflammatory responses and immunogenicity in comparison with type I collagen. We demonstrate that bone mesenchymal stem cells-laden co-assembled hydrogel can be stably fixed in rabbit knee joint defects by photocuring, which significantly facilitates hyaline cartilage regeneration after three months. This co-assembly strategy provides an approach for developing cartilage regenerative biomaterials.

寡肽和多肽分子的组装可以通过分子间相互作用重建各种有序的高级结构，从而实现类蛋白质的生物功能。在这里，我们开发了一种受“分子尼龙搭扣”启发的肽和明胶共组装策略，其中两亲性超分子三肽通过分子内/间相互作用连接到明胶甲基丙烯酰的分子链上。我们进行了分子对接和动力学模拟，以证明该策略的可行性，并揭示了共组装水凝胶的先进结构转变，这带来了更有序的β-折叠含量和10倍或更多的抗压强度提高。我们进行转录组分析，以揭示共组装水凝胶在促进细胞增殖和软骨分化中的作用。皮下植入评估证实，与 I 型胶原相比，炎症反应和免疫原性显着降低。我们证明，负载骨间充质干细胞的共组装水凝胶可以通过光固化稳定地固定在兔膝关节缺损中，这显着促进了三个月后透明软骨的再生。这种共组装策略为开发软骨再生生物材料提供了一种方法。