The RNA delivery dilemma - lipid versus polymer nanoparticle platforms

Abstract

Since the first market authorization of RNA therapies, just eight years ago, the field has witnessed an extraordinary expansion, ranging from hepatic delivery for rare genetic diseases to global-scale vaccination during the COVID-19 pandemic, and now to cutting-edge cancer vaccines and gene editing strategies entering late-stage clinical trials. In parallel, the RNA therapeutics landscape has evolved rapidly, progressing from small interfering RNAs to next-generation and combinatorial RNA modalities. None of these breakthroughs would have been possible without the development of sophisticated RNA delivery technologies capable of navigating complex biological environments, enabling precise cellular targeting, and facilitating efficient intracellular trafficking. In this Editorial Note, we take a step back to reflect on key lessons learned throughout the RNA delivery journey. Featuring insights from leading and experienced voices in the field, this manuscript highlights critical milestones, persistent challenges, and the roles of lipid nanoparticles (LNPs) and polymer nanoparticles (PNPs) as RNA delivery platforms. These experts reflect on the features that have positioned LNPs as the current RNA delivery gold standard, while also exploring the untapped potential and distinctive advantages of polymer-based nanosystems. Collectively, these perspectives underscore a striking truth: we are only beginning to unlock the full therapeutic potential of RNA, and nanomedicine will certainly continue to shape the future clinical translation of RNA-based therapies.

Introduction

The field of RNA delivery has witnessed remarkable progress over the past decade, with nanomedicine emerging as a key enabler in bringing these therapies to the clinic. This is because, for RNA-based gene therapies to be effective, therapeutic RNA must reach the intracellular milieu of target cells while avoiding off-target toxicity. However, due to their inherently high molecular weight and anionic nature, RNAs cannot readily traverse the cell membrane and typically require a delivery system [1, 2]. A longstanding dilemma in the field focuses on the advantages and limitations of lipid nanoparticles (LNPs) and polymeric nanoparticles (PNPs) as the most suitable non-viral delivery systems for this purpose.

LNPs are currently the most established RNA delivery platform, largely due to their central role in the development of COVID-19 vaccines and their expanding use in a wide range of diseases. Their impact builds on decades of research, as highlighted in a recent review by Pieter Cullis and Philip Felgner, two pioneers in lipid-based nucleic acid delivery, who summarized the historical contributions of LNPs over the past six decades [3]. Philip Felgner is also widely recognized for his discovery of Lipofectamine, one of the earliest and most influential synthetic lipid formulations for transfection, which paved the way for many of today’s delivery technologies [4]. LNPs emerged from foundational work on liposomes, a concept introduced by Bangham et al. in 1965 [5], and subsequent refinements established the four-component architecture of modern LNPs: ionizable amino lipids, helper lipids (e.g., phospholipids and zwitterionic lipids), sterols, and polyethylene glycol (PEG) lipids. A major advancement came with the addition of ionizable lipids, which transformed their delivery potential, leading to potency increases of up to 1,000-fold compared with earlier lipid systems [6]. Ionizable lipids are key to the function of LNPs in delivering RNA into cells: while uncharged in neutral environments, their positively chargeable head determines the LNP pKa, enabling both nucleic acid encapsulation and interaction with anionic endosomal membranes [7]. Together with Pieter Cullis, whose work laid the foundation for clinically approved LNP systems, Robert Langer and Daniel Anderson are widely regarded as leaders at the forefront of lipid-based drug delivery [8,9,10,11]. With decades of pioneering work behind them, they have recently advanced the field further by applying machine learning to accelerate the discovery of new ionizable lipids [12].

In addition to LNPs, less attention has been paid to different types of polymers that can be used to formulate PNPs for RNA delivery [13,14,15,16]. Like ionizable lipids, many polymers used in PNP formulations carry a positive charge, allowing them to interact with and compact negatively charged RNA into stable particles. These polymers often feature a mix of primary, secondary and tertiary amine groups, which can enhance cellular uptake and promote release from endosomes. However, their overall positive surface charge tends to attract negatively charged serum proteins, which can compromise physiological stability. Among polymer-based nanosystems, polyethyleneimine (PEI) has long been the most widely studied, though its high cytotoxicity has prompted the search for safer alternatives [17,18,19,20]. Thanks to their chemical versatility, polymers offer a promising delivery platform beyond the liver, with the potential to be tailored for a wide range of therapeutic needs. Ongoing efforts to design new polymer structures that meet the specific physicochemical demands of RNA delivery are likely to expand the toolkit available for future gene therapies.

As RNA therapeutics evolve toward increasingly complex applications, such as the co-delivery of large and small RNAs or even combinations of RNA and DNA, there is growing interest in pushing the limits of current nanoparticle (NP) platforms. Efforts are focused on fine-tuning the ratios and chemistries of lipid components or adjusting polymer backbones or side chains to create formulations that can better handle this diversity. At the same time, not every therapeutic need fits comfortably within the LNP framework. Certain applications demand features like nuclear transport, tunable targeting, prolonged release features or improved stability, and these are areas where lipid systems still face limitations. Polymers, with their vast chemical flexibility and unique ability to condense RNA via multivalent interactions, remain compelling candidates to fill these gaps. Though they are earlier in their clinical development, PNPs may offer the potential for controlled release formulations, enhanced stability and broader targeting capabilities. However, realizing this promise requires continued advances in materials science and mechanistic understanding, delivery strategies, safety, and standardization.

These evolving challenges and opportunities will be explored in depth through the expert perspectives featured in this article. This article includes perspectives from Professors Michael Mitchell, Dan Peer, Yvonne Perrie, Daniel Siegwart, and María José Alonso, world-leading experts in the field of RNA delivery.

Michael Mitchell is Associate Professor in the Department of Bioengineering at the University of Pennsylvania as well as the Leader of the Lipid Nanoparticle Delivery Systems Group and the Director of the Lipid Nanoparticle Synthesis Core, both located at the Penn Institute for RNA Innovation. At the interface of biomaterials science, drug delivery and cellular and molecular bioengineering, the Mitchell lab focuses on the synthesis of novel biomaterials and NPs for the delivery of nucleic acids (siRNA, miRNA, mRNA, CRISPR-Cas9) for cancer therapy; engineering of immune cells for immunotherapy and vaccines; investigating the influence of biomaterial chemical structure on in vivo transport to target cells and tissues; and novel drug delivery technologies for tissue engineering and regenerative medicine.

Dan Peer is Professor of Nanomedicine and Immunology at Tel Aviv University and the director of the Laboratory of Precision NanoMedicine at the same University. He is also the Founder and Managing Director of the SPARK Tel Aviv Center for Translational Medicine and has been elected member of the Israel Young Academy, US National Academy of Engineering and Fellow of the US National Academy of Inventors and the Controlled Release Society (CRS). The Peer lab works at the interface of materials science, chemistry, molecular biology, and immunology, to discover and validate novel therapeutic targets at the molecular level, and to develop specific genetic medicines for therapeutics and disease management. His lab pioneered work in developing cell-type specific delivery strategies of novel RNA and DNA molecular medicines, and novel genome editing strategies. In addition, the lab has generated a very large library of structurally unique lipids, some of which have been tested clinically as carriers for different types of RNAs as novel vaccines and therapeutics.

Yvonne Perrie is Professor and the Chair in Drug Delivery within Strathclyde Institute for Pharmacy and Biomedical Sciences at the University of Strathclyde. She is also a Fellow of the Society of Biology, a Fellow of the Royal Society of Chemistry, the Royal Pharmaceutical Society and an Eminent Fellow of the Academy of Pharmaceutical Sciences. Moreover, she has been president of CRS and a Member of the Order of the British Empire for services to pharmaceutical innovation and regulation. The Perrie Lab focuses on the design, formulation, and manufacture of nanomedicines, developing practical solutions to address current healthcare challenges.

Daniel J. Siegwart is Professor in the Department of Biomedical Engineering, Department of Biochemistry, and the Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center. He holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research and serves as the Director of the Program in Genetic Drug Engineering and Director of the Drug Delivery Program in Biomedical Engineering. The Siegwart lab uses a materials chemistry approach to enable targeted NP delivery of genomic medicines. Notably, his lab has been at the forefront in the design of synthetic carriers for gene editing and has applied these technologies for correction of genetic diseases and treatment of cancer.

María José Alonso is Full Professor at the University of Santiago de Compostela and a fellow of the American Institute for Medical and Biological Engineering and of the CRS. She was also president of the CRS (2018–2020) and a member of three Academies in Spain, the US National Academy of Medicine, the Royal Academy of Medicine of Belgium, and the Academy of Pharmacy and Biochemistry of Argentina. María José Alonso’s lab has pioneered the design and development of novel nanostructures based on biopolymers intended to the targeted delivery of drugs, notably biological drugs. More specifically, in the field of vaccination, her lab has collaborated in the development of needle-free vaccination strategies for several vaccines, including a series of mRNA nasal vaccines.

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Martins, C., Mitchell, M.J., Peer, D. et al. The RNA delivery dilemma—lipid versus polymer nanoparticle platforms. Drug Deliv. and Transl. Res. (2026). https://doi.org/10.1007/s13346-026-02044-6