A Microalgae‐Based Dual‐Pathway Therapy for Simultaneous Ammonia Detoxification and Colorectal Cancer Suppression

Abstract Ammonia dysregulation is a common pathological feature linking hyperammonemia—a severe metabolic disorder‐ and colorectal cancer (CRC), yet current treatment options remain inadequate. Here, a first‐in‐class dual‐pathway ammonia scavenging system is introduced based on a bioengineered microalgae‐hydrogel oral formulation (SPB‐CV@ALG), designed to simultaneously treat hyperammonemia and suppress CRC progression. This multifunctional system integrates Chlorella vulgaris (CV), capable of biologically capturing intestinal ammonia via extracellular adsorption and intracellular assimilation, with sodium phenylbutyrate (SPB), a clinically approved metabolic ammonia scavenger. These agents are co‐encapsulated within a semi‐interpenetrating sodium alginate–carboxymethyl chitosan hydrogel, which enhances gastrointestinal retention, protects biological activity, and ensures colon‐targeted release. In murine hyperammonemia models, SPB‐CV@ALG significantly lowered systemic ammonia levels, rescued cognitive and behavioral deficits, and mitigated hepatic and cerebral pathology. Remarkably, the same formulation also inhibited tumor growth in both subcutaneous and orthotopic CRC models. Mechanistically, the therapy reshaped gut microbiota composition by enriching beneficial taxa such as Akkermansia muciniphila and depleting pro‐tumorigenic Pseudomonadota , supporting a microbiota‐mediated anti‐cancer mechanism. Long‐term safety studies confirmed favorable biocompatibility without systemic toxicity. This study presents a transformative therapeutic paradigm that leverages microalgae's natural metabolic functions for dual‐disease intervention. The SPB‐CV@ALG platform offers a safe, effective, and translational solution to address two major unmet clinical needs through integrated ammonia detoxification, tumor suppression, and microbiome modulation.