Replacing PEG in lipid nanoparticles (LNPs) marks a critical evolution in the development of safer and more effective nucleic acid delivery systems. While PEG has long been the gold standard for nanoparticle stabilization, its association with immunogenicity and reduced efficacy upon repeat dosing has sparked a growing shift toward alternative polymers. Emerging materials like polysarcosine and poly(2-oxazoline)s offer comparable stealth and formulation performance, without triggering unwanted immune responses, paving the way for next-generation RNA therapeutics and gene delivery platforms.
The PEG Paradigm and the need for Change
Over the past decade, lipid nanoparticles (LNPs) have emerged as a crucial technology in the delivery of RNA-based therapeutics, vaccines, and other gene editing tools. One fairly common part of these systems is polyethylene glycol (PEG), a polymer that has long been considered the gold standard for nanoparticle stabilization, circulation time extension, and immune evasion.
PEGylated lipids have played a key role in the success of multiple approved LNP products being the most well known the mRNA COVID-19 vaccines and siRNA drugs like Onpattro®. PEG’s inclusion in these systems improves colloidal stability, modulates particle size, and delays opsonization by immune cells, earning thanks to all of this advantages PEG has positioned indispensable excipient in nanomedicine.
However, with the popularization of its use has come growing concerns. Recent evidence now points to a series of safety and efficacy concerns related to PEG’s immunogenic profile. Repeated dosing may trigger the formation of anti-PEG antibodies, increasing nanoparticle clearance from the bloodstream, this is commonly known as the “accelerated blood clearance” (ABC) effect. Moreover, hypersensitivity reactions and potential anaphylaxis have prompted regulatory agencies to issue black-box warnings and re-evaluate PEG’s long-standing reputation as an inert polymer.
These challenges have pushed a renewed search for next-generation polymers that can replicate or even surpass PEG’s functional role, without the immunological problems. This new NanoTalks post explores the most promising PEG alternatives for LNP delivery systems, with a particular focus on polysarcosine (PSar) and other emerging candidates. We’ll discuss their structural features, biological performance, and clinical potential as the field transitions toward safer, smarter, and more sustainable drug delivery platforms.
1. The Immunogenicity Challange
The widespread use and popularization of PEGylated lipid nanoparticles has unveiled a complex and underappreciated barrier: the immune system doesn't always ignore PEG.
Multiple studies have reported the presence of anti-PEG antibodies, both IgM and IgG isotypes, in from 20% up to 70% of the general population. These antibodies can be naturally occurring or induced upon first exposure to PEG-containing formulations, from cosmetics, processed foods, and common pharmaceuticals. leading to rapid immune recognition in subsequent doses.
The clinical consequences are twofold:
- Accelerated Blood Clearance (ABC): Repeated administration of PEGylated particles leads to their rapid removal by the mononuclear phagocyte system (MPS), especially in the liver and spleen, undermining efficacy.
- Complement Activation and Hypersensitivity: Some individuals experience complement activation-related pseudoallergy (CARPA), manifesting as infusion reactions or even anaphylaxis. This has been documented in responses to both PEGylated liposomes and mRNA-LNP vaccines.
Mechanistically, the immune recognition is driven not just by anti-PEG antibodies, but also by protein corona formation, which can alter the surface profile of PEG-coated nanoparticles, further promoting opsonization and clearance.
What’s more, these effects are patient-dependent and hard to predict, complicating dose scheduling and clinical trial interpretation. The variability in PEG reactivity is becoming a critical obstacle in RNA therapy, gene editing, and protein delivery platforms that rely on repeated dosing.
These findings have intensified the demand for non-immunogenic alternatives, materials that retain PEG’s stealth and stability but without triggering unwanted immune responses.
2. What Makes a good Peg Alternative?
Replacing PEG is not as simple as changing one polymer for another. PEG plays a highly specific role in lipid nanoparticle (LNP) formulations: it increases colloidal stability, prevents aggregation during storage and injection, reduces protein adsorption, prolongs circulation time, and influences particle size and polydispersity. Any potential alternative should be able to play the same role replicatewithout triggering immune responses.
So, what defines an effective PEG replacement in the context of LNP-based delivery systems?
- Biocompatibility and Immunological safety
The ideal polymer must avoid recognition by the immune system, not only lacking immunogenicity itself, but also minimizing the formation of anti-polymer antibodies or complement activation. This means avoiding repetitive ethylene oxide units (a known epitope for anti-PEG antibodies), and ideally mimicking naturally occurring or zwitterionic structures.
- Stealth and Circulation Time
Like PEG, the polymer should impart “stealth” properties, resisting opsonization, protein corona formation, and clearance by the mononuclear phagocyte system. It should support prolonged blood circulation and allow sufficient time for accumulation in target tissues (e.g., via the EPR effect or active targeting).
- Stability and Size Control
The polymer must enable tight control over nanoparticle size (<200 nm), low polydispersity, and colloidal stability over time. In microfluidic or ethanol injection methods, it should behave predictably during self-assembly.
- Scalable and Reproducible Synthesis
Any candidate must be synthetically accessible, with low batch-to-batch variability, GMP-compatible production methods, and ideally modular chemistry that allows for surface modification or ligand attachment.
- Regulatory and Manufacturing Compatibility
Finally, the polymer should be compatible with existing regulatory frameworks, analytical methods, and manufacturing infrastructure. Ease of integration into current LNP workflows is critical for translational success.
This set of criteria is guiding the development of PEG alternatives such as polysarcosine (PSar), poly(2-oxazoline)s, and zwitterionic polymers, each bringing its own balance of stealth, safety, and scalability. We’ll explore them next.
3.Leading Candidates: A Closer Look at PEG Alternatives
The urgent need for safer, non-immunogenic alternatives to PEG has incentivized a wave of innovation in polymer science. Several classes of hydrophilic polymers are now being evaluated as stealth components in lipid nanoparticles (LNPs), each offering distinct advantages in terms of biocompatibility, stealth capacity, and synthetic flexibility. Below, we take a deeper look at some of the most promising candidates
the clinical stage. This milestone underscores the growing confidence in PSar as a clinically viable alternative to PEG, opening the door for broader adoption across RNA, peptide, and small molecule delivery platforms.
3.1 Zwitterionic polymers
Such as poly(carboxybetaine), are gaining attention for their exceptional antifouling properties. These materials carry both positive and negative charges, which create a net-neutral, highly hydrated surface that resists protein adsorption and immune recognition. In theory, this makes them ideal stealth candidates for LNP coatings. Early studies suggest they may outperform PEG in avoiding complement activation and cellular uptake by immune cells. However, their application in LNP formulations remains largely theoretical at this stage, with very limited in vivo data and no progression toward clinical evaluation as yet.
3.2 Poly(2-oxazoline)s (POx)
Poly(2-oxazoline)s (POx) represent another highly promising alternative to PEG in nanoparticle-based drug delivery. These synthetic polymers are prized for their exceptional tunability: by adjusting the oxazoline monomer type, chain length, and terminal functionalities, researchers can precisely modulate their hydrophilicity, molecular weight, and overall pharmacokinetics. This level of modularity allows for the fine-tuning of LNP surface characteristics, resulting in improved colloidal stability, prolonged circulation times, and enhanced tissue-specific delivery.
In the context of mRNA delivery, POx-coated LNPs have demonstrated outstanding performance. Preclinical studies have reported not only enhanced mRNA stability and efficient cellular uptake but also reduced formation of anti-polymer antibodies , a key limitation of PEG-based systems. In some animal models, POx-LNPs have even shown superior protein expression in targeted organs compared to PEG-LNPs, suggesting that POx may support both improved delivery and therapeutic efficacy.
Importantly, the chemical structure of POx is inherently less immunogenic and more biodegradable than PEG, which could make it safer for repeated administration. While most current applications remain in the preclinical pipeline, the clinical landscape is beginning to shift. A POx-based formulation, although not an LNP, has already entered clinical trials for the treatment of Parkinson’s disease, establishing a regulatory and translational precedent that could accelerate the adoption of POx for RNA-based therapies. As interest in PEG alternatives continues to grow, POx stands out for its versatility, favorable safety profile, and expanding clinical relevance.
3.3 Polysarcosine (PSar)
Polysarcosine (PSar) has emerged as one of the front-runners in the race to replace PEG. Structurally, it is a nonionic, hydrophilic polypeptoid derived from the endogenous amino acid sarcosine. Its stealth properties are comparable to PEG, but with a significantly lower risk of immunogenicity. Unlike PEG, PSar is biodegradable and does not accumulate in tissues, reducing concerns around long-term exposure. PSar-based lipids and excipients have been incorporated into LNP formulations with promising outcomes: comparable particle sizes, high encapsulation efficiencies, and robust mRNA expression in preclinical models. Notably, PSar-LNPs have shown reduced secretion of inflammatory cytokines and lower complement activation compared to PEG-LNPs, a key advantage for chronic or repeat-dose therapies.
Curapath has developed PSar under GMP conditions, enabling integration into clinical-grade formulation development. Meanwhile, companies like Lubrizol are actively advancing PSar-based delivery systems. In fact, Lubrizol’s Apisolex™ platform, which leverages polysarcosine to enhance solubility and bioavailability of injectable drugs, has recently entered Phase I clinical trials , marking the first PSar-containing systems to reach Clinical trials.
3.4 Emerging synthetic hydrophilic polymers
Other synthetic hydrophilic polymers are also being explored as potential PEG replacements, though they remain at an earlier stage of development. This includes traditional vinyl-based polymers such as poly(N-vinylpyrrolidone) (PNVP) and poly(N-methyl-N-vinylacetamide) (PNMVA), which are water-soluble, biocompatible, and widely used as pharmaceutical excipients. Their long track record of clinical use supports their safety, and preliminary studies suggest they may elicit fewer anti-polymer antibodies than PEG. However, they have not yet been widely tested in the context of LNP-mediated RNA delivery.
Similarly, methacrylate-derived polymers such as POEGMA, PHPMA, and PDMA offer modular platforms that can be tuned for stealth, responsiveness, or enhanced biocompatibility. POEGMA mimics the structure of PEG while resisting protein adsorption; PHPMA has a strong history in polymer–protein conjugation; and PDMA has been used in pH-responsive formulations. While these materials have shown promising results in vitro, including enhanced mRNA expression and stability, there is currently a lack of in vivo data validating their performance in LNP systems, and none have entered clinical development for RNA delivery to date.
4.Case Study: PSar–VitE as a PEG-Free Excipient in LNPs
One of the most advanced examples of PEG replacement in LNP systems is the development of PSar–VitE, a proprietary shielding lipid designed by Curapath to mimic and improve upon the functional role of PEG-lipids such as DMG-PEG2000. Polysarcosine (PSar), a biocompatible polypeptoid, is conjugated to vitamin E to anchor into the lipid bilayer, creating a stealth-like surface that minimizes protein adsorption and immune activation. This design enables compatibility with standard LNP formulations, while offering a more favorable immunological profile.
Preclinical data has demonstrated that PSar–VitE can maintain the critical properties of PEG-based LNPs, including high encapsulation efficiency, narrow size distribution, and colloidal stability. In side-by-side comparisons, LNPs formulated with various PSar–VitE constructs showed comparable or improved size control and polydispersity index, despite the higher molar content of PSar needed relative to PEG. Notably, encapsulation efficiencies across all tested formulations remained consistently high (>90%), underscoring the platform’s robustness.
Comparative formulation data for lipid nanoparticles (LNPs) incorporating either DMG-PEG or polysarcosine–vitamin E (PSar–VitE) as the shielding lipid. All formulations share the same ratios of ionizable lipid, DSPC, and cholesterol, with a fixed nitrogen-to-phosphorus (N/P) ratio of 6.2. Despite the higher molar percentage of PSar–VitE (5%) compared to DMG-PEG (1.6%), all PSar–based LNPs maintained high encapsulation efficiency (EE%) and acceptable polydispersity index (PDI). Notably, particle sizes varied across formulations, demonstrating the tunability of PSar–VitE systems.
Beyond physical stability, PSar–VitE has shown promising biological performance. In vitro and in vivo studies revealed efficient cellular uptake, potent gene expression, and, importantly, a reduction in proinflammatory cytokine release and complement activation, issues that have increasingly come under scrutiny with PEG-containing systems. In vivo biodistribution studies confirmed that PSar–based LNPs maintained comparable tissue targeting to PEG systems, while offering enhanced transfection in several organs, including liver and spleen. These findings suggest PSar–VitE is not only functionally equivalent, but may offer superior performance in repeat-dose settings or immunologically sensitive applications.
Furthermore, the scalability and synthetic reproducibility of PSar–VitE have been validated under GMP conditions. SEC profiles confirmed the ability to precisely control polymer chain length and molecular weight distribution across production batches and scales (from 1 g to 100 g), a key requirement for clinical translation.
The platform was further enhanced through strategic collaboration with Certest, integrating PSar–VitE with Certest’s proprietary ionizable lipids. This joint formulation demonstrated synergistic benefits: improved mRNA delivery efficiency, high encapsulation (>95%), and particle sizes below 200 nm. Remarkably, the combined system also proved resilient to freeze–thaw cycles and long-term lyophilized storage, maintaining biological activity for over a year at 4°C and 25°C—critical for real-world distribution and stockpiling.
These data position PSar–VitE as one of the most clinically ready and versatile PEG alternatives currently available. While formal clinical trials are still pending, the preclinical validation, GMP production readiness, and successful performance in complex formulations (e.g., mRNA vaccines, siRNA, circRNA) make it a highly promising component for next-generation LNP systems.
5.Challenges to Clinical Translation
While preclinical data on PEG alternatives is increasingly compelling, the path toward clinical adoption is neither immediate nor straightforward. Several critical challenges remain before polymers like PSar, POx, or zwitterionic materials can fully replace PEG in approved lipid nanoparticle (LNP) formulations.
One of the most significant barriers is regulatory familiarity and inertia. PEG has been used in pharmaceuticals for decades and benefits from a long-established safety record, despite emerging concerns. In contrast, even the most promising alternatives, such as polysarcosine or poly(2-oxazoline)s, lack extensive human safety data. Regulatory agencies will require rigorous evidence of toxicology, biodistribution, metabolism, and immunogenicity before these materials can be incorporated into commercial products. For developers, this translates into longer timelines, higher costs, and more complex formulation work during early-stage development.
Another obstacle is the manufacturing scale-up and reproducibility of alternative polymers. Unlike PEG, which is widely available from multiple GMP-certified suppliers with consistent physicochemical properties, many novel polymers are still manufactured in research-grade facilities, often with limited batch-to-batch reproducibility or unclear supply chains. Controlling polymer architecture, especially molecular weight, dispersity, and end-group chemistry, is critical for ensuring consistency in pharmacokinetics and biodistribution, particularly in sensitive systems like RNA therapeutics.
There is also a formulation compatibility challenge. PEG-lipids have been optimized for use in LNPs through decades of iteration, and their behavior during nanoparticle self-assembly, particularly in microfluidic or ethanol injection processes, is well understood. PEG alternatives must not only match these properties but do so under the same manufacturing conditions and equipment. Subtle differences in hydrophilicity, chain flexibility, or anchor-lipid chemistry can significantly affect particle size, polydispersity, encapsulation efficiency, and colloidal stability.
Lastly, developers must navigate the clinical design implications of transitioning away from PEG. Most regulatory guidelines, biodistribution models, and immunogenicity assays have been built around PEGylated systems. Introducing a new shielding polymer introduces new variables into clinical trial design, from dosing and administration schedules to immuno-monitoring protocols and analytical validation strategies.
Despite these hurdles, the shift away from PEG is accelerating. With growing awareness of PEG-related safety concerns, especially in repeat-dose applications, and increasing availability of GMP-grade alternatives like PSar, the field is entering a transitional phase. Successful clinical translation will depend on collaborative efforts betweenConclusion
As RNA-based therapies and gene delivery platforms mature, the limitations of PEG are becoming impossible to ignore. Immunogenicity, reduced efficacy upon redosing, and patient variability are prompting the field to rethink its reliance on this decades-old polymer. Fortunately, a new generation of alternatives—led by polysarcosine, poly(2-oxazoline)s, and other synthetic stealth polymers, is emerging to meet this challenge.
While regulatory and manufacturing hurdles remain, the data are clear: PEG-free formulations can match, and in some cases exceed, the performance of PEG-based systems. With scalable GMP production, robust preclinical validation, and growing momentum from both academia and industry, the path toward safer, smarter, and more sustainable LNPs is already being built, one polymer at a time.
When exploring PEG-free LNP solutions for your RNA or gene therapy programs, make sure you have access to the right excipients, formulation know-how, and GMP manufacturing support.
