Methods and compositions are provided for gently lysing and solubilizing cells. Methods and compositions are further provided for quickly purifying high quality low molecular weight nucleic acid from host cells. Target cells are treated with a pre-chilled lysis solution having a zwitterionic detergent, for example n-Dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, and a brief room-temperature incubation. Where nucleic acid purification is required, the lysis solution-treated cells are contacted with a nucleic acid capture matrix having an average pore size of at least about 1 μm.