Table 1.

Hurdles faced by PBAEs as gene delivery vehicles.

Disadvantages	Strategies for Overcoming Challenge
Uncontrolled/off-target nucleic acid release	Triggered release by external stimulus [72]
	Triggered intracellular release by cleavage of disulfide bonds [30,36,41,42,49,73,74]
	Nuclear localization signal (NLS) for DNA trafficking to nucleus [35]
	Surface receptor ligand for nanoparticle accumulation at target cell type [35,82–86]
Encapsulation of anionic cargo only	Addition of chemical groups to improve hydrogen bonding and hydrophobic interactions with other cargo [54]
Toxicity due to excessive positive charge	Blending with anionic or less highly charged polymer [55,113]
	Shielding of the surface with ligands, peptides, or PEG [55,76]
Poor transport through tissue due to excessive positive charge	Shielding of the surface with ligands, peptides, or PEG [52,57,76,80]
Immune response	Selection of applications that require immune activation [60,87]
Low nucleic acid binding efficiency	Incorporation of other polymers with high positive charge density [40]
	Use of high ratios of PBAE to nucleic acid [30,39,41,42]
	Engineering of branched nucleic acids with high avidity [46]
	Synthesis of branched PBAEs with high avidity [47–49]
Low colloidal stability in physiological fluids	Non-covalent functionalization with PEG [52,80]
	Covalent functionalization with PEG [76]
	Blending with anionic or less highly charged polymer [55,113]
Poor stability during storage or transport	Lyophilization with lyoprotectants [31,33–38]