Cell membrane-engineered nanoparticles, integrating the functions of the natural cell membrane and synthetic nanoparticles, are of great interest in various biomedical applications. In particular, cell membrane-engineered hybrid soft nanocomposites (CMHSNCs) with the core of degradable macromolecules or biofunctional molecules, and the shell of various types of functional cell membranes exhibited superior biocompatibility, prolonged circulation and enhanced targeting. They have been explored for cancer therapy, bioimaging, detoxification, anti-virulence and thrombolysis. Herein, recent advances on CMHSNCs are reviewed for delivery of various cargoes including drugs, genes, peptides, proteins, antigens/adjuvants, photoactivatable agents and probes. In addition, the challenges and possible future directions of the CMHSNCs for fundamental research and clinical translation are discussed.