Tetracycline (TC) residues from anthropogenic activities undesirably present in nature as an emerging sustainability challenge and thereby require innovations in remediation technologies. Herein, as inspired by the microcompartment structure in living organisms, we adopt a synthetic biology approach to engineer the FerTiG, a modular enzyme assembly, to robustly scavenge TC residues with improved performance. The FerTiG consists of three functional modules, namely, a TC degradation module (Tet(X4)), a cofactor recycling module glucose dehydrogenase (GDH) , and a protection module (ferritin), to organize diverse catalytic processes simultaneously as a biological circuit. The incorporation of GDH suitably fuels the FerTiG-dependent TC degradation by regenerating expensive nicotinamide adenine dinucleotide phosphate (NADPH) cofactor with glucose. The ferritin shields the catalytic core of FerTiG to resiliently decompose TC under unfavorable conditions. Due to collaboration among functional modules, FerTiG strongly catalyzes the residual TC removal from multiple environmental matrices. The degradation pathways and environmental/biological safety of FerTiG are then elaborated, indicating the promising readiness for the application of FerTiG. In summary, this work presents a synthetic biology-based strategy to spontaneously impose residual antibiotic biodegradation for better sustainability management. The FerTiG is engineered as a proof-of-principle for TC removal; however, this ‘microcompartment-mimicking’ concept is of great interest in mitigating other sustainability challenges where modular catalytic machinery is applied.

• FerTiG is designed as a multienzyme complex to degrade tetracycline residues;

• GDH module fuels FerTiG to spontaneously degrade tetracycline residues;

• Ferritin module renders FerTiG resilient to the environmental stresses;

• FerTiG robustly eliminated tetracycline from multiple environment matrices;

• FerTiG displays no eco- or biosafety concerns for application.