Aptamers for drug delivery: from targeting concept to the clinic

argeted delivery has become one of the most active directions in aptamer research. Aptamers can act as molecular addresses, recognizing a receptor on a specific cell and carrying another therapeutic component with them.

The concept has now been demonstrated with many types of payloads: doxorubicin, gemcitabine, paclitaxel and docetaxel; siRNA and other nucleic acids; liposomes; polymeric and metallic nanoparticles; and increasingly complex multifunctional constructs. Recent reviews describe a rapidly expanding landscape of aptamer–drug conjugates and aptamer-targeted delivery systems, particularly in oncology.

From proof of concept to clinical translation

Some of the foundational work dates back almost two decades. In 2006, researchers including Omid Farokhzad and Robert Langer demonstrated PSMA-targeting A10 aptamer-functionalized nanoparticles carrying docetaxel in prostate-cancer models. In that study, complete tumor reduction was observed in 5 of 7 mice treated with the targeted formulation, compared with 2 of 7 receiving the non-targeted nanoparticle formulation.

Another important molecule has been AS1411, an aptamer targeting nucleolin. AS1411 itself was developed as a therapeutic rather than a delivery vehicle, but its ability to recognize and internalize into cancer cells subsequently made it one of the most widely explored targeting aptamers for drug and nanoparticle delivery. It was also the first anticancer aptamer tested in humans: Aptamera initiated the first Phase I study, and Antisoma later advanced it into Phase II trials. A Phase II renal-cell carcinoma trial enrolled 35 patients.

The aptamer class itself has also achieved clinical validation. Macugen (pegaptanib), developed by Eyetech and partnered with Pfizer, became the first FDA-approved aptamer therapeutic in 2004. Izervay (avacincaptad pegol), developed by Iveric Bio and now part of Astellas, became another FDA-approved RNA aptamer in 2023; its approval was supported by trials involving 625 patients. These drugs are not delivery conjugates, but they demonstrate that chemically modified aptamers can be developed, manufactured and used clinically.

Aptamer–drug conjugates are now reaching patients

Perhaps the most significant recent development for targeted delivery is AST-201 from Aptamer Sciences.

AST-201 targets GPC3, a cell-surface protein highly expressed in several cancers, particularly hepatocellular carcinoma. The aptamer incorporates the anticancer drug gemcitabine, binds GPC3-positive tumor cells and is designed to deliver the active drug intracellularly following internalization. The underlying approach showed selective activity in GPC3-positive cancer cells and tumor inhibition in mouse xenograft models before moving toward clinical development.

Aptamer Sciences began dosing patients in 2025, and AST-201 is now listed in a Phase I, first-in-human study in patients with GPC3-positive advanced solid tumors, including hepatocellular carcinoma and non-small-cell lung cancer. The study is evaluating safety, pharmacokinetics and preliminary antitumor activity.

That transition is important: aptamer-mediated drug delivery is moving from an extensive preclinical literature toward actual clinical testing of an aptamer–drug conjugate.

But binding is only the beginning

The field still faces important bottlenecks.

A delivery aptamer must do considerably more than bind strongly. It must recognize the correct cells in vivo, access the target in complex tissues, internalize efficiently and retain useful pharmacokinetics. For intracellular cargos such as RNA, cellular uptake creates another challenge: endosomal escape may still limit how much therapeutic material reaches its intended intracellular destination.

Small aptamers can penetrate tissue efficiently, but their size can also cause rapid renal clearance. Chemical modification, PEGylation, multivalent constructs or incorporation into nanoparticles can improve pharmacokinetics — while simultaneously making the final system more complex to manufacture and characterize. Recent reviews therefore identify stability, biodistribution, off-target effects, conjugation chemistry and scalable manufacturing among the major barriers to clinical translation.

Designing for delivery, not just affinity

This may ultimately be the key evolution in the field.

An aptamer intended for drug delivery should not necessarily be developed as a high-affinity binder first and converted into a delivery molecule afterwards. Internalization, selectivity in the relevant biological environment, cargo compatibility and the final therapeutic function can all be considered during selection and optimization.

That shift — from finding binders to selecting molecules for a defined biological function — is one of the reasons aptamer-mediated drug delivery is becoming such an interesting area for next-generation SELEX.

For the references, I would link directly to the strongest examples: AST-201 Phase I clinical trial · Aptamer Sciences AST-201 platform and pipeline · GPC3 aptamer–gemcitabine preclinical study · Landmark PSMA aptamer–docetaxel nanoparticle study · 2025 review of aptamers in targeted drug delivery · 2025 review of aptamer–drug conjugates

I think this version works much better for Nemrod because it says “this is a hot and increasingly credible field” without overselling it as already clinically established.