A highly programmable platform for sequential release of protein therapeutics

Drug carriers capable of releasing multiple protein therapeutics in an appropriate sequence are highly desirable for the treatment of many diseases. However current systems only allow the sequential release of two or three proteins, and it is difficult to adjust the time intervals between them. Here to solve these problems a new system is designed. The proteins are first encapsulated in CaCO₃ microspheres. Then the microspheres are coated with hydrogen-bonded tannic acid (TA)/polyethylene glycol (PEG) layer-by-layer films. The encapsulated protein does not release from the microsphere until the TA/PEG coating is fully disintegrated. As the TA/PEG coating is eroded at a constant rate, the lag time for protein release is proportional to the coating thickness. To achieve sequential release, one can simply coat the protein-encapsulated microspheres with different thickness TA/PEG films and then mix them. Both in vitro and in vivo tests demonstrate that the proteins can be released from the mixed samples in a sequence according to the thickness of the TA/PEG coatings. The time intervals between the protein releases can be facilely adjusted by adjusting the thickness of the TA/PEG coatings. In addition, sequential release of more than 3 proteins can be facilely achieved.