Abstract: A method for overcoming the packaging limitations of recombinant adeno-associated virus (AAV) particles through AAV heterodimer formation is provided. In the method, an expressed nucleic acid, typically a portion of a gene encoding a full-length therapeutic protein, or a functional derivative thereof, is split into two or more fragments by the insertion of one or more introns. Each intron is then split and each of the gene portions are inserted between AAV ITRs for packaging into recombinant adeno-associated virus particles. The recombinant viral particles are then co-infected into a target cell. Once inside the cell, the viral vectors form head-to-tail heterodimers through sequence homology of the inverted terminal repeats, thereby re-forming the intron. During mRNA maturation, the intron is spliced from the continuous DNA molecule, removing the intron and, thus, the intervening ITR sequences, thereby restoring the precise coding sequence of the expressed nucleic acid.