Design of Single‐Atom Nanozymes for Precision Treatment of Erectile Dysfunction with Integrated Single‐Cell RNA Sequencing and Machine Learning

ABSTRACT Patients with diabetes mellitus‐induced erectile dysfunction (DMED) usually suffer more severe symptoms, and efficacy of the first‐line therapy is limited. This study develops an integrated framework combining single‐cell RNA sequencing (scRNA‐seq) and machine learning (ML) to design nanozymes with specific enzyme‐mimicking types for precision treatment of DMED. First, scRNA‐seq analysis demonstrated increased reactive oxygen species (ROS) level and downregulated expression level of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) in the corpus cavernosum of DMED patients. Second, a nanozyme database is constructed based on the published researches. With this database, two ML models are developed to predict the enzyme‐mimicking types of nanozymes, which showed that iron (Fe)‐based nanozymes are particularly suitable for addressing reductase deficiencies in DMED. Thus, the Fe‐DMOF, an Fe‐based single atom nanozyme (SAzyme), is synthesized, simultaneously exhibiting GPx‐, CAT‐ and SOD‐like activities. Fe‐DMOF can significantly reduce the ROS accumulation and inhibit the ROS‐induced histone lactylation modifications, furtherly reversing the inflammatory differentiation of fibroblasts and macrophages in the diabetic corpus cavernosum. These results not only highlight the efficacy of Fe‐DMOF in DMED treatment, but also validate the scRNA‐seq + ML framework as an effective approach for data‐driven SAzyme design for disease‐specific treatment.