Abstract

Polyethylene glycol (PEG)-lipid conjugates have emerged as indispensable components in nanoparticle-based drug delivery systems, enabling advances in oncology, infectious diseases and gene therapy. By combining a hydrophilic PEG chain with a hydrophobic lipid moiety (e.g., DMG, DSPE), these amphiphilic molecules impart nanoparticles with enhanced stability, prolonged circulation time, and modifiable surface functionality—key attributes for clinical translation. In this review, we summarize the structural roles of PEG lipids in nanoparticle design, highlight their pivotal applications in emerging therapeutics, discuss current challenges, and explore future directions. For researchers and industry partners engaging in next-generation nanoparticle platforms, a clear understanding of PEG lipid functionality is essential.

1. Introduction: The Structural Foundation of PEG Lipids in Nanoparticles

PEG lipids are covalent conjugates of polyethylene glycol (a biocompatible, non-ionic polymer) and lipid anchors (e.g., phosphoethanolamines, glycerides, cholesterol derivatives). Their amphiphilic design enables spontaneous insertion into nanoparticle membranes or lipid‐based carriers, where they perform three core functions:

• Steric stabilization: The PEG chains form a hydrated shell around nanoparticles, reducing aggregation and inhibiting non-specific protein adsorption. PMC+2RSC出版+2
•  Pharmacokinetic optimisation: By reducing recognition and clearance by the mononuclear phagocyte system (MPS), PEG lipids help extend nanoparticle circulation half-lives—hence the term “stealth” agents. PMC+1
• Functional tunability: The terminal end groups of PEG (e.g., amine, carboxyl, azide) can be used to link targeting ligands, imaging moieties or stimuli-responsive elements, thereby enhancing specificity or providing additional functionality.

Among the widely used PEG lipids are DSPE-PEG₂₀₀₀ (valued for membrane anchoring) and DMG-PEG₂₀₀₀ (frequently used in mRNA vaccine LNPs). Their broad utility has made them foundational in lipid nanoparticle (LNP) formulations which now underpin approved therapeutics. PMC+1

2. Key Applications of PEG Lipids in Therapeutic Nanoparticles

2.1 Nucleic Acid Delivery: mRNA Vaccines and RNA Therapeutics

PEG lipids came into global prominence as critical components of the mRNA vaccine LNP platform (e.g., in COVID-19 vaccines). In registered LNP formulations, PEG-lipid conjugates typically account for a small molar fraction (e.g., ~0.5–3 mol% of the lipid mixture). Their presence safeguards the mRNA payload, stabilises the particle and improves systemic circulation. PMC+1

Recent work has shown that structural parameters of PEG-lipids (such as lipid tail length and PEG content) have measurable impacts on mRNA translation efficiency, biodistribution and immune activation. For instance, one study found that PEG-lipid content above ~3 mol% reduced encapsulation efficiency and lowered in vivo expression. PubMed

Beyond vaccines, PEG lipids are central to LNPs delivering siRNA (e.g., for hereditary amyloidosis) or gene‐editing cargoes directed at hematopoietic stem cells. While proprietary formulation details often remain unpublished, the general principle is that PEG lipids help stabilise the nanoparticle while other lipids provide ionisable or fusogenic functionality.

2.2 Cancer Therapy: Targeted Chemotherapy and Immunotherapy

In oncology, PEG lipids help overcome limitations of free chemotherapeutics by enabling liposomal or nanoparticle formulations with improved pharmacokinetics. The prototypical example is Doxil (pegylated liposomal doxorubicin), which uses a PEG-lipid-modified shell to extend circulation and exploit the enhanced permeability and retention (EPR) effect in tumours. PMC+1

Targeted delivery is also achieved by appending ligands (e.g., RGD peptides) to PEG termini on lipids (e.g., DSPE-PEG-RGD), directing nanoparticles to receptors such as integrins (αᵥβ₃) over-expressed in tumour vasculature or cells. This targeted approach can increase local drug concentration several-fold versus untargeted carriers.

Combination of PEG-lipid formulations with immunotherapy (for instance LNPs encapsulating checkpoint inhibitors or immune-modulators) further enhances tumour accumulation and reduces systemic toxicity—though many of these are still in pre-clinical or early‐clinical stages.

2.3 Mucosal and Ocular Drug Delivery: Overcoming Physiological Barriers

Administration via mucosal (nasal, intestinal) or ocular routes presents challenges: mucociliary clearance, mucus entrapment, tight epithelial junctions. PEG lipids, especially when combined with other functional moieties (e.g., chitosan, targeting ligands), have shown promise for enhancing nanoparticle penetration and retention at such sites. For example, chitosan-modified PEG lipids in intranasal mRNA formulations achieved higher secretory IgA responses versus unmodified LNPs (in pre-clinical models).

In ocular delivery, PEG lipid variants with altered terminal charges (e.g., carboxyl-modified PEG) have been explored to improve photoreceptor transfection in retinal gene therapy models. While specific peer‐reviewed data are still emerging, the general trend supports PEG lipid optimisation to tailor tropism and barrier penetration.

2.4 Formulation Optimization: Tailoring PEG Lipids for Specific Needs

The performance of PEG lipids depends critically on structural parameters: PEG chain length (e.g., PEG₂₀₀₀ vs PEG₅₀₀₀), lipid tail saturation and length (e.g., C14 vs C18), surface density (mol % of total lipids), and the nature of the linker (ester, carbamate, disulfide) or terminal group.

Studies show, for example, that short‐chain lipid anchors (e.g., C14) dissociate faster from the nanoparticle membrane in serum, altering protein-corona formation and biodistribution. PMC+1

Similarly, too high a PEG-lipid molar percentage may hinder cellular uptake or endosomal escape, whereas too low may reduce “stealth” behavior. Optimisation methods such as Design-of-Experiments (DoE) are increasingly used to identify ideal molar ratios, PEG lengths and anchor lipid types that maximize payload delivery while minimising clearance.

3. Challenges and Emerging Solutions

Despite their widespread utility, PEG lipids and PEGylation strategies still face key limitations:

3.1 Immunogenicity and Accelerated Blood Clearance (ABC)

Evidence indicates that repeated administration of PEGylated particles may lead to the generation of anti-PEG antibodies, which in turn accelerate clearance of subsequent doses (the so-called “ABC” phenomenon) or induce complement activation-related pseudo-allergy (CARPA). PubMed

While the general population appears to tolerate single-dose PEGylated products well (e.g., mRNA vaccine carriers), the impact on repeated dosing, chronic therapies or high-dose regimens remains a topic of active investigation. For example, a human cohort study found no clear reduction in efficacy of mRNA vaccines in the presence of anti-PEG antibodies, though the area remains under-studied. PubMed

Emerging solutions: use of alternative “stealth” polymers (e.g., polysarcosine, poly(carboxybetaine)), cleavable PEG-lipids that detach in situ, or anchoring designs that minimise immunogenic exposure of PEG termini.

3.2 Trade-offs Between Stealth and Uptake / Endosomal Escape

While PEG provides stealth and prolonged circulation, high PEG densities or too long PEG chains may hamper cellular uptake or endosomal escape, reducing intracellular delivery efficiency. RSC
Solutions:

• Use of “cleavable” PEG-lipids (e.g., disulfide-linked PEG that cleaves in reductive environments) to regain uptake post-circulation.
• Use of lower PEG molar percentages (< 1 mol %) to balance stealth and uptake.
• Tailoring lipid anchors and linker chemistry to allow controlled PEG shedding upon reaching target tissue.

4. Future Directions: Next-Generation PEG Lipid Nanoparticles

Looking ahead, three major trends can be anticipated:

• Personalised formulation: Using AI/ML-driven DoE models to predict optimal PEG-lipid parameters (chain length, ligand density, anchor lipid) for individual patients or disease indications.
• Dual-functional PEG lipids: Conjugates that combine targeting ligands (e.g., galactose, peptides) plus imaging/tracking agents (e.g., FITC, radiolabel) on PEG termini—enabling theranostics and real-time biodistribution monitoring.
• Sustainable manufacturing & novel polymers: Use of plant-derived lipid anchors, bio-based PEG alternatives (e.g., polyglycerol, polysarcosine) and greener synthetic processes to meet GMP standards with reduced environmental impact. Frontiers

5. Conclusion

PEG lipids have become cornerstone components of modern nanoparticle delivery systems, enabling the translation of mRNA vaccines, targeted chemotherapies and gene therapies into clinical practice. Their capacity to modulate nanoparticle stability, circulation time and tropism makes them irreplaceable tools for researchers and industry scientists optimizing nanoparticle performance. While issues such as immunogenicity and the balance between circulation vs uptake remain, emerging alternatives and smarter design strategies promise to unlock further potential. For academics, biotech and pharmaceutical collaborators alike, advancing PEG-lipid design and implementation will be pivotal for the next wave of nanomedicine innovation.