共价有机框架（COFs）近期展现出在癌症治疗领域的巨大应用前景，但其组装系统面临相当大的挑战，如用于体内给药和释放的疏水和亲水蛋白质药物的共递送，以及蛋白质药物的逃逸过内质体/溶酶体等问题。为解决这些问题，我们利用硼酸酯键连接的COFs（COF-1）的高比表面积、亲脂性和结构可调性，构建了先进的药物传递系统。我们首先将小分子药物多柔比星（DOX）封装到疏脂性COF中（COF-1@DOX），并将功能性蛋白质药物核糖核酸酶A（RNase A）固定在COF的表面上（RNase A-COF-1@DOX）。然后，我们通过交联白蛋白氧化水凝胶（gel）网络到COFs的孔隙中，构建了一种新型复合传递系统（RNase A-COF-1@DOX gel），实现了体内靶向共递送蛋白质和小分子药物。通过体内多通道荧光显像，我们分析了在路易斯肺癌（LLC）模型中的体内蛋白质和小分子药物的共递送。最后，我们应用RNase A-COF-1@DOX gel对治疗小鼠的肺癌进行了研究。本研究为构建基于COF的肺癌药物传递系统铺平了道路，并有潜力扩展到其他类型的癌症治疗，以实现更有效和靶向的治疗。

Covalent organic frameworks (COFs) have revealed enormous application prospects for cancer therapeutics recently, but their assembly systems face considerable challenges, such as the codelivery of hydrophobic and hydrophilic protein drugs with different physicochemical properties for in vivo delivery and release, as well as endosomal/lysosomal escape of protein drugs. To address these issues, we leveraged the high specific surface area, lipotropism, and structural tunability of boronate ester-linked COFs (COF-1) for the construction of advanced drug delivery systems. We first encapsulated the small-molecule drug doxorubicin (DOX) into a lipophilic COF (COF-1@DOX) and immobilized the functional protein drug ribonuclease A (RNase A) on the surface of the COF (RNase A-COF-1@DOX). We then created a novel composite delivery system (RNase A-COF-1@DOX gel) by cross-linking an albumin-oxygenated hydrogel (gel) network into the pores of COFs, allowing targeted codelivery of protein and small-molecule drugs in vivo. Using in-living body and multichannel fluorescence imaging, we analyzed the in vivo codelivery of protein and small-molecule drugs in a Lewis lung carcinoma (LLC) model. Finally, we applied the RNase A-COF-1@DOX gel to treat lung cancer in mice. This study paves an avenue for constructing COF-based drug delivery systems for lung cancer treatment and holds the potential to be extended to other types of cancer for more effective and targeted therapeutic treatments.