Targeting nucleic acid-based therapeutics to tumors: Challenges and strategies for polyplexes

The current medical reality of cancer gene therapy is reflected by more than ten approved products on the global market, including oncolytic and other viral vectors and CAR T-cells as ex vivo gene-modified cell therapeutics. The development of synthetic antitumoral nucleic acid therapeutics has been proceeding at a lower but steady pace, fueled by a plethora of alternative nucleic acid platforms (from various antisense oligonucleotides, siRNA, microRNA, lncRNA, sgRNA, to larger mRNA and DNA) and several classes of physical and chemical delivery technologies. This review summarizes the challenges and strategies for tumor-targeted nucleic acid delivery. Focusing primarily on polyplexes (polycation complexes) as nanocarriers, delivery options across multiple barriers into tumor cells are illustrated.