Nucleic acid nanotechnologies: transforming the future of precision medicine

The convergence of chemistry, molecular biology, nanotechnology, and computational sciences has created unique opportunities for transformative therapeutics and biomedical devices that are rapidly reshaping modern healthcare [1]. In this dynamic landscape, nucleic acids (RNA and DNA) have emerged as key players in natural sciences and nanomedicine. Beyond their well-known fundamental roles in storing and regulating the flow of genetic information, nucleic acids have offered a diverse toolset for understanding disease mechanisms, aiding the development of innovative therapeutic platforms and precision diagnostics that together address urgent healthcare challenges.

Modern nanomedicine leverages the unique physicochemical properties and functions of conventional nucleic acids, as well as a plethora of their synthetic chemical analogs, with an increasing number of interdisciplinary research teams entering the field and exploring how these biopolymers can be safely applied to modulate intracellular biological pathways in human cells. Numerous classes of therapeutic nucleic acids (TNAs), such as microRNAs (miRNAs), antisense oligonucleotides (ASOs), aptamers, small interfering RNAs (siRNAs), messenger RNAs (mRNAs), and CRISPR-based systems, have entered clinical development, with dozens of technologies approved for the treatment of various diseases [2].

However, despite numerous success stories, the translational potential of TNAs remains hindered by several limitations stemming from their inefficient delivery and cellular uptake, the chemical instability of naked TNAs, uncontrolled immune activation and general toxicity, as well as challenges associated with manufacturing and scalability [3,4]. While chemical instability can be addressed through a variety of nucleic acid modifications [5] and efficient delivery with cellular uptake largely relies on use of carefully selected carriers [6], next-generation TNAs are being developed to overcome other limits by reducing toxicity, expanding the number of targetable pathways, enhancing target specificity, and increasing intracellular activity. Together, these advancements enable lower dosage of TNAs and development of personalized formulations for precision medicine, ultimately improving clinical outcomes [7–9]. In these next-gen TNAs, RNA and DNA molecules are rationally designed to self-assemble into predefined modular nanoarchitectures, termed nucleic acid nanoparticles, or NANPs, each endowed with unique physicochemical properties, biological activities, and multiple functionalities [9]. The inherent ability of DNA, and more so of RNA, to form both canonical and non-canonical base-pairing interactions allows for generation of an expanding repertoire of structural and long-range interacting motifs that can be organized in different ways, much like Lego^® blocks, to produce self-assembling NANPs with programmable geometries and predefined functions [10].

Although engineered de novo, artificial NANPs are recognized by living systems as biologically compatible entities, enabling these exogenous formulations to effectively interface with human cells and modulate intracellular pathways [7–9]. Moreover, the uncovered design principles tackle fundamental questions addressing the relationship between nucleic acids’ structure and function, the biophysics governing their folding, and the chemical interactions between nucleic acids and other classes of molecules in vitro and in biological matrices. The gained knowledge, together with the high modularity and tunability of NANPs, positions this core biotechnology as a versatile platform for broad-spectrum diagnostic, therapeutic, and regenerative medicine applications.

One of the most dynamic areas of investigation involves nucleic acid nanotechnology for improved drug delivery and minimized off-target effects. The broader therapeutic uses of RNA- and DNA-based therapies are diminished by the inability of negatively charged nucleic acids to cross biological membranes. Therefore, new, more efficient delivery methods for nucleic acids that leverage synthetic and natural carriers to overcome these barriers would need to be developed. When multiple therapeutic cargoes are required based on an individual patient’s profile, they can be rationally integrated into programmable NANP scaffolds, enabling coordinated, cell-specific delivery with precise spatiotemporal control. This modular approach allows combination therapies to be customized to the genetic and molecular characteristics of each patient, advancing the implementation of precision medicine. The combinations of these functional architectures and tailored delivery carriers can further optimize pharmacokinetics, improve tissue penetration, and enable controlled TNA release in response to intracellular disease-associated signals, including elevated oncogene expression profiles [8]. Such capabilities are particularly attractive for precision oncology, personalized treatment of infectious diseases, and bioimaging.

Another rapidly advancing area is nucleic acid-based immunotherapy. While the immunotoxicity and immunomodulatory effects of TNAs were poorly understood and had been a major impediment, especially to bringing more RNA-based drugs into clinical trials, recent discoveries indicate that NANPs can be rationally designed to modulate innate and adaptive immune responses through the controlled presentation of immunostimulatory motifs and therapeutic cargo [11]. Importantly, accumulating evidence also indicates that NANPs themselves are not just passive scaffolds but can be engineered for regulated immune recognition through careful optimization of their structural parameters and chemical composition [5,12,13]. This unique capability positions NANPs as a new class of multifunctional therapeutics that may function as inert excipients, active pharmaceutical ingredients, or combinations of both, depending on their composition and intended biomedical application [14]. This notion of multifunctional and context-dependent nature of NANPs calls for innovative research strategies and updated regulatory frameworks that need to be extended way beyond the traditional API/excipient paradigm. The development and implementation of such frameworks are critical for enabling the safe and effective clinical translation of nucleic acid nanotechnologies with proven therapeutic potential.

In the past decade, deep learning has driven significant advances across various research fields, from computer vision to natural language processing. Based on numerous recent collaborative efforts, several machine learning (ML) and artificial intelligence (AI)-guided tools have been developed to computationally identifying optimal nucleic acid nanostructures and aligning them with desired biological outcomes to accelerate the development of personalized therapeutic approaches [15–17]. In future works, emphasis would be placed on emerging areas including proactive integration of AI/ML-guided nucleic acid nanotherapeutic design and structure activity relationship studies aimed at understanding critical quality attributes and establishing quality-by-design industrial standards [18,19].

Other emerging areas utilize nucleic acid nanomaterials in biosensor development to increase detection sensitivity using programmable RNA and DNA nanoprobes that enhance recognition of various analytes and pathogens in biological samples [20]. However, issues related to biosensing in complex biological environments, shelf-life, and stability still need to be addressed.

Overall, as nucleic acid nanotechnology enters a new era of personalized therapies, this burgeoning field is rapidly expanding beyond proof-of-concept studies toward more defined bimedical applications. Recent progress and developments in extracellular vesicles, AI-enabled nanomaterial design, theranostics, immunoengineering, gene delivery, and scalable nanoformulations are transforming how versatile nucleic acid-based systems are designed, manufactured, and transitioned from laboratory discovery to clinical implementation. Continued progress will depend on integrating advances in programmable nanodesign, synthesis, characterization, improved in vivo stabilities, regulated immunotoxicity, and scalable manufacturing with a deeper understanding of biological interactions and medical needs. In addition, the rapid progress of the field calls for new training programs that integrate RNA and DNA nanotechnology with complementary disciplines, including computational and molecular biology, immunology, toxicology, pharmacology, gene therapy, and nanomedicine, to fully realize the transformative potential of TNAs. Together, these interdisciplinary efforts are paving the way for next-generation nucleic acid nanotechnologies capable of enabling personalized diagnostics, targeted therapeutics, and improved outcomes across a broad range of human diseases.