MXenes belong to a new class of two dimensional (2D) functional nanomaterials, mainly encompassing transition‐metal carbides, nitrides and carbonitrides, with unique physical, chemical, electronic and mechanical properties for various emerging applications across different fields. To date, the potentials of MXenes for biomedical application such as drug delivery have not been thoroughly explored due to the lack of information on their biocompatibility, cytotoxicity and biomolecule‐surface interaction. In this study, we developed novel drug delivery system from MXene for the controlled release of a model therapeutic protein. First, the structural, chemical and morphological properties of as synthesized MXenes were probed with electron microscopy and X‐ray diffraction. Second, the potential cytotoxicity of MXene toward the proliferation and cell morphology of murine macrophages (RAW 264.7) were evaluated with MTT assays and electron microscopy, respectively. Moreover, the drug loading capacities and sustained release capabilities of MXene were assessed in conjunction with machine learning approaches. Our results demonstrated that MXene did not significantly induce cellular toxicity at any concentration below 1 mg/ml which is within the range for effective dose of drug delivery vehicle. Most importantly, MXene was efficiently loaded with FITC‐catalase for subsequently achieving controlled release under different pHs. The release profiles of catalase from MXene showed higher initial rate under basic buffer (pH 9) compared to that in physiological (pH 7.4) and acidic buffers (pH 2). Taken together, the results of this study lead to a fundamental advancement toward the use of MXene as a nanocarrier for therapeutic proteins in drug delivery applications.

Oxidative stress, overproduction of reactive oxygen species (ROS), plays an important role in the development of inflammatory bowel diseases. Catalase has great therapeutic potential by scavenging hydrogen peroxide, one of the ROSs produced in cellular metabolisms. However, in vivo application to scavenge ROS is currently limited especially in oral administrations. Here, we introduced an alginatebased oral drug delivery system that effectively protected catalase from the simulated harsh conditions of the gastrointestinal (GI) tract, released it in the small intestine mimicked condition, and enhanced its absorption via M cells, highly specialized epithelium cells in the small intestine. First of all, catalase was encapsulated in alginate-based microparticles with different amounts of polygalacturonic acid or pectin, which achieved an encapsulation efficiency of more than 90%. It was further shown that catalase was released from alginate-based microparticles in a pHdependent manner. Results indicated that alginate-polygalacturonic acid microparticles (60 wt % Alg:40 wt % Gal) released 79.5 ± 2.4% of encapsulated catalase at pH 9.1 in 3 h, while they only released 9.2 ± 1.5% of encapsulated catalase at pH 2.0. Even when catalase was encapsulated in microparticles (60 wt % Alg:40 wt % Gal) and exposed to pH 2.0 followed by pH 9.1, it still retained 81.0 ± 11.3% enzyme activity compared to that in microparticles prior to the pH treatment. We then investigated the efficiency of RGD conjugation to catalase on the catalase uptake by M-like cells, the coculturing of human epithelial colorectal adenocarcinoma; Caco-2 cells and B lymphocyte; Raji cells. RGD-catalase protected M-cells more efficiently from the cytotoxicity of H 2 O 2 , a typical ROS. RGD conjugation to catalase enhanced the uptake by M-cells with 87.6 ± 0.8% RGD-catalase, whereas 11.5 ± 9.2% of RGD-free catalase passed across M-cells. From the results of protection, release, and absorption of model therapeutic proteins from the harsh pH conditions, alginatebased oral drug delivery systems will have numerous applications for the controlled release of drugs that are easily degradable in the GI tract.