Beyond conventional therapies: Gut microbiota modulation and macromolecular drugs in the battle against cardiometabolic diseases.

Cardiometabolic diseases (CMDs) represent an ongoing major global health challenge, driven by complex interactions among genetic, environmental, microbiome-related, and other factors. While small-molecule drugs and lifestyle interventions can provide clinical benefits, they are possible to be constrained by the limited druggability of key target proteins, the potential risks of off-target effects, and difficulties in maintaining long-term adherence. In recent years, gut microbiota modulation and macromolecular drugs have emerged as promising therapeutic strategies. Gut microbiota modulation (e.g., probiotics, synbiotics, or natural products) exerts systemic metabolic and immune effects, supporting a therapeutic approach targeting multiple diseases. Meanwhile, macromolecular drugs (e.g., peptides, antibodies, and small nucleic acids) offer precise, pathway-targeted interventions. Despite advancements, limitations remain in addressing ethical considerations in microbiota modulation and optimizing targeted delivery systems, all of which may hinder clinical translation. Here, we provide a comprehensive overview of therapeutic approaches for CMDs, with a focus on obesity, type 2 diabetes mellitus (T2DM), and atherosclerosis (AS). The review is structured around three key aspects: i) conventional therapies, including small-molecule drugs and lifestyle interventions; ii) emerging therapies encompassing gut microbiota modulation, macromolecular drugs, and their interactions; and iii) challenges and opportunities for comorbidity management, microbiota ethics, and artificial intelligence (AI)-driven therapeutic optimization. We hope this review enhances the understanding of small-molecule drugs, lifestyle interventions, gut microbiota modulation, and macromolecular drugs in the management of CMDs, thereby fostering medical innovation and contributing to the development of system-based comprehensive therapeutic paradigms.