Uploaded August 2026 | Updated September 2026, 2 weeks ago
Efficient and targeted delivery remains one of the biggest obstacles for nucleic acid therapeutics. Due to these challenges, most nucleic acid-based therapeutics to date target the liver, because it’s where these biologics tend to go “naturally” and/or are easiest to direct to (thankfully, the liver is the site of a lot of metabolic activity and also makes a lot of proteins for the bloodstream, so targeting the liver can have wider effects than just influencing the liver itself); Blood cells – often because blood cells can be removed, treated ex vivo, and returned to a patient; and “isolated” organs (eyes, ears, brain, etc.) that can be injected into (local administration) and are protected from immune attack.
Depending on the size of the nucleic acid cargo, the target cells, and whether delivery is occurring in vivo or ex vivo, there are a few main strategies for delivery:
Viral vectors – these involve the use of harmless viruses stripped down to their bare necessities (e.g. genes needed to produce proteins to allow the viruses to inject genetic instructions into cells) and filled with desired cargo. They take advantage of virus’ natural ability to infect cells and deliver nucleic acids (a process called transduction) and are typically used for delivery of genes (but that could include a gene for making a miRNA or shRNA!). Limitations of viral vectors include:; Pre-existing immunity to the viruses causing immunogenicity (i.e. the vector itself sets of an immune response in the recipient that can be harmful on its own and/or can prevent the cargo delivery); Developed immunity to the viruses after the first administration can prevent subsequent re-administration.; Limited payload capacity – may not be able to hold all the genetic info needed.; Too limited or too broad of tropism (tropism refers to what cells a virus can infect).
- 3 main classes: lentiviruses (e.g. HIV-based retroviruses); adenoviruses; and adeno-associated viruses (AAVs)(type of parvoviruses)
Lipid NanoParticles (LNPs): these are greasy “bubbles” that encapsulate the nucleic acid (or other molecular) cargo and help them get into cells.Their main components are typically:
1) Cationic (positively-charged) or ionizable (chargeable) lipid
2) Helper lipid (typically a glycerophospholipid)
3) PEG (polyethylene glycol)-lipid
4) Cholesterol
The exact components and their amounts can be optimized for different applications, and a lot of work is underway to try to optimize LNPs to target specific tissues and/or cell types. LNPs often go mainly to the liver due to the binding of LNPs to a blood protein called apolipoprotein E (apoE), which binds to a low-density lipoprotein (LDL) receptor on liver cells, prompting their internalization into the liver cell through endocytosis. (Endocytosis is a process whereby a cell basically pinches off a part of its membrane (and whatever it’s attached to) and “swallows” it, bringing the membrane-bound contents into the cell, at first trapped in an endosome bubble that they can then escape from (but this escape from the endosome can itself be a large delivery hurdle to overcome!).)
GalNAc conjugation: GalNAc (N-acetylgalactosamine) is a type of sugar molecule that can be attached (conjugated) to nucleic acid therapeutics (especially small ones) to target them to the liver (specifically to hepatocytes). They bind to the liver cells’ asialoglycoprotein receptors (ASGPR) and then get internalized by endocytosis. Inside the cells, the GalNAc gets cleaved off.
Virus-Like Particles (VLPS): These don’t contain any viral DNA, just the viral shell
Electroporation: This strategy, almost always performed ex vivo or in vitro, involves the use of electric pulses to take advantage of nucleic acids’ negative charges to coax them into cells.
There are many technologies in development, some of which involve the use of cell-type-specific antibodies that target the therapeutics to specific cell types based on “recognizing” molecules on the target cells’ surfaces.
Much more here: thebumblingbiochemist.com/biopharmaceutical-sciences
Recommended reading:
Geng et al. Viral and Non-Viral Vectors in Gene Therapy: Current State and Clinical Perspectives. eBioMedicine 2025, 118. doi.org/10.1016/j.ebiom.2025.105834.
Hosseini-Kharat, Bremmell, and Prestidge. Why Do Lipid Nanoparticles Target the Liver? Understanding of Biodistribution and Liver-Specific Tropism. Molecular Therapy Methods & Clinical Development 2025, 33 (1). doi.org/10.1016/j.omtm.2025.101436.
Debacker et al. Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug. Molecular Therapy 2020, 28 (8), 1759–1771. doi.org/10.1016/j.ymthe.2020.06.015.
More on in vivo, ex vivo, etc.: thebumblingbiochemist.com/365-days-of-science/in-where-in-vitro-in-vivo-ex-vivo-in-situ-in-silico-when-it-comes-to-what-happens-where-heres-what-there-is-to-know
Efficient and targeted delivery remains one of the biggest obstacles for nucleic acid therapeutics. Due to these challenges, most nucleic acid-based therapeutics to date target the liver, because it’s where these biologics tend to go “naturally” and/or are easiest to direct to (thankfully, the liver is the site of a lot of metabolic activity and also makes a lot of proteins for the bloodstream, so targeting the liver can have wider effects than just influencing the liver itself); Blood cells – often because blood cells can be removed, treated ex vivo, and returned to a patient; and “isolated” organs (eyes, ears, brain, etc.) that can be injected into (local administration) and are protected from immune attack.
Depending on the size of the nucleic acid cargo, the target cells, and whether delivery is occurring in vivo or ex vivo, there are a few main strategies for delivery:
Viral vectors – these involve the use of harmless viruses stripped down to their bare necessities (e.g. genes needed to produce proteins to allow the viruses to inject genetic instructions into cells) and filled with desired cargo. They take advantage of virus’ natural ability to infect cells and deliver nucleic acids (a process called transduction) and are typically used for delivery of genes (but that could include a gene for making a miRNA or shRNA!). Limitations of viral vectors include:; Pre-existing immunity to the viruses causing immunogenicity (i.e. the vector itself sets of an immune response in the recipient that can be harmful on its own and/or can prevent the cargo delivery); Developed immunity to the viruses after the first administration can prevent subsequent re-administration.; Limited payload capacity – may not be able to hold all the genetic info needed.; Too limited or too broad of tropism (tropism refers to what cells a virus can infect).
- 3 main classes: lentiviruses (e.g. HIV-based retroviruses); adenoviruses; and adeno-associated viruses (AAVs)(type of parvoviruses)
Lipid NanoParticles (LNPs): these are greasy “bubbles” that encapsulate the nucleic acid (or other molecular) cargo and help them get into cells.Their main components are typically:
1) Cationic (positively-charged) or ionizable (chargeable) lipid
2) Helper lipid (typically a glycerophospholipid)
3) PEG (polyethylene glycol)-lipid
4) Cholesterol
The exact components and their amounts can be optimized for different applications, and a lot of work is underway to try to optimize LNPs to target specific tissues and/or cell types. LNPs often go mainly to the liver due to the binding of LNPs to a blood protein called apolipoprotein E (apoE), which binds to a low-density lipoprotein (LDL) receptor on liver cells, prompting their internalization into the liver cell through endocytosis. (Endocytosis is a process whereby a cell basically pinches off a part of its membrane (and whatever it’s attached to) and “swallows” it, bringing the membrane-bound contents into the cell, at first trapped in an endosome bubble that they can then escape from (but this escape from the endosome can itself be a large delivery hurdle to overcome!).)
GalNAc conjugation: GalNAc (N-acetylgalactosamine) is a type of sugar molecule that can be attached (conjugated) to nucleic acid therapeutics (especially small ones) to target them to the liver (specifically to hepatocytes). They bind to the liver cells’ asialoglycoprotein receptors (ASGPR) and then get internalized by endocytosis. Inside the cells, the GalNAc gets cleaved off.
Virus-Like Particles (VLPS): These don’t contain any viral DNA, just the viral shell
Electroporation: This strategy, almost always performed ex vivo or in vitro, involves the use of electric pulses to take advantage of nucleic acids’ negative charges to coax them into cells.
There are many technologies in development, some of which involve the use of cell-type-specific antibodies that target the therapeutics to specific cell types based on “recognizing” molecules on the target cells’ surfaces.
Much more here: thebumblingbiochemist.com/biopharmaceutical-sciences
Recommended reading:
Geng et al. Viral and Non-Viral Vectors in Gene Therapy: Current State and Clinical Perspectives. eBioMedicine 2025, 118. doi.org/10.1016/j.ebiom.2025.105834.
Hosseini-Kharat, Bremmell, and Prestidge. Why Do Lipid Nanoparticles Target the Liver? Understanding of Biodistribution and Liver-Specific Tropism. Molecular Therapy Methods & Clinical Development 2025, 33 (1). doi.org/10.1016/j.omtm.2025.101436.
Debacker et al. Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug. Molecular Therapy 2020, 28 (8), 1759–1771. doi.org/10.1016/j.ymthe.2020.06.015.
More on in vivo, ex vivo, etc.: thebumblingbiochemist.com/365-days-of-science/in-where-in-vitro-in-vivo-ex-vivo-in-situ-in-silico-when-it-comes-to-what-happens-where-heres-what-there-is-to-know
