Enzymes in living organisms work efficiently in confined environments through spatial organization. Constituting a bio-cascade reaction in nano-confined space in vitro for the efficient synthesis of high-value chiral chemicals is challenging. Herein, we confined a cofactor-dependent cascade in bacteriophage P22 nanoparticles for the synthesis of chiral alcohols. Compared to free enzymes, this supramolecular ensemble, P22-SP-BmGDH-SsCR, exhibited enhanced catalytic efficiency up to 14.5-fold towards various ketones and improved stereoselectivity up to > 99% ee towards 8 substrates, and 10 chiral alcohols with > 96% ee were synthesized. The recycling efficiency of nicotinamide adenine dinucleotide phosphate (NADPH) was increased by 7.5-fold. We demonstrated that the enhancement in cofactor recycling originates from the higher local concentration of NADPH in the nanoparticles due to the proximity effect of enzymes and confinement of nanoparticles. The preparative synthesis of chiral alcohols showed that the consumption of NADPH can be reduced by one magnitude compared with the conventional free enzyme system.