Intracellular delivery of various drugs, including DNA, and drug carriers can sharply increase the efficiency of various treatment protocols. However, the receptor-mediated endocytosis of drugs, drug carriers, and DNA results in their lysosomal delivery and significant degradation. The problem can be solved and therapy efficacy still further increased if the approaches for direct intracytoplasmic delivery that bypass the endocytic pathway are developed. This is especially important for many anticancer drugs (proapoptotic drugs whose primary action site is the mitochondrial membrane) and gene therapy (nuclear or mitochondrial genomes should be targeted). This review considers several current approaches for intracellular drug delivery: the use of pH-sensitive liposomes, the use of cell-penetrating proteins and peptides, and the use of immunoliposomes targeting intracellular antigens. Among intracellular targets, nuclei (gene therapy), mitochondria (proapoptotic cancer therapy and targeting of the mitochondrial genome), and lysosomes (lysosomal targeting of enzymes for the therapy of the lysosomal storage diseases) are considered. Examples of successful intracellular and organelle-specific delivery of biologically active molecules, including DNA, are presented; unanswered questions, challenges, and future trends are also discussed.
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