📄 chemistry

Several aspects of poly(D,L-lactide-co-glycolide) nanoparticles surface modification via a layer-by-layer method

This paper investigates the layer-by-layer surface modification of PLGA nanoparticles, highlighting the necessity of preliminary steric stabilization and analyzing how polyelectrolyte ratios, molecular weights, and specific polymer combinations influence the resulting physicochemical properties of the multifunctional delivery systems.

Original authors: Ekaterina Kuznetsova, Mikhail Vantsyan, Kirill Kalinin, Tatiana Bukreeva, Sergei Chvalun

Published 2026-09-01

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CC BY 4.0

Original authors: Ekaterina Kuznetsova, Mikhail Vantsyan, Kirill Kalinin, Tatiana Bukreeva, Sergei Chvalun

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

Imagine a world where tiny, biodegradable capsules could deliver medicine directly to a sick cell, releasing their payload only when and where it is needed. This is the promise of polymeric nanoparticles, microscopic carriers made from materials that the body can safely break down. Among the most promising of these carriers is a substance called PLGA, a plastic-like polymer that can be shaped into spheres small enough to travel through the bloodstream. However, for these spheres to be truly useful as drug delivery vehicles, scientists must be able to coat them with a protective, functional skin. This skin, built layer by layer, can control how fast a drug is released, hide the particle from the immune system, or help it find its target. The challenge lies in applying this skin without causing the tiny spheres to clump together into useless lumps or growing so large that they can no longer navigate the body's narrow pathways.

In a recent study, researchers at the Kurchatov Institute in Moscow tackled the specific problem of how to successfully apply this protective skin to PLGA nanoparticles. They focused on a technique called layer-by-layer assembly, where oppositely charged molecules are attracted to the surface of the particle like magnets, building up a shell one layer at a time. The team discovered that the success of this process depends entirely on how the particles are prepared before the coating begins. They found that if the nanoparticles are left in their raw, uncoated state, the moment they try to attract the first layer of coating material, the particles lose their stability. Instead of accepting a neat, thin layer, they crash into one another, forming large, irregular clumps that are too big and too messy to be useful. The solution, they found, was to first wrap the nanoparticles in a thin, invisible shield of a substance called poly(vinyl) alcohol. This preliminary step acts as a buffer, keeping the particles apart and stable in water, which allows the subsequent coating layers to attach smoothly and evenly without causing a collision.

Once the particles were properly stabilized with this initial shield, the researchers tested how different factors influenced the final result. They varied the amount of coating material added, the size of the coating molecules, and even the type of material used, including both synthetic chemicals and natural protein-like chains. They found that once there was enough coating material to cover the surface completely, adding more did not change the size or stability of the particles; the surface simply became saturated, and the extra material washed away. However, the size of the coating molecules mattered significantly. When they used very large, long-chain molecules for the second layer of the shell, the particles grew noticeably larger, swelling to nearly double their original size. The researchers suggest this happened because these long chains trapped water and expanded, creating a looser, bulkier shell. In contrast, using smaller molecules kept the shell compact.

Perhaps most importantly, the team demonstrated that they could build a multi-layered shell using a combination of synthetic materials and natural polypeptides, which are chains of amino acids similar to those found in the body. This approach allowed them to construct a sophisticated, multi-layered structure without causing the particles to clump or grow too large. The final coated particles remained relatively small, with a diameter of roughly 240 after the first coating layer, and maintained a uniform size distribution, which is critical for medical applications. However, the study noted that when using specific high-molecular-weight combinations, the size could increase significantly to around 400 nm, highlighting the need to carefully select materials to keep the particles within the preferred size range. The study concludes that while the layer-by-layer method is powerful, it requires a careful foundation. By first stabilizing the nanoparticles with a protective layer, scientists can successfully build complex, functional skins on these tiny carriers, paving the way for more precise and effective drug delivery systems that can navigate the human body with ease.

Technical Summary: Aspects of Poly(D,L-lactide-co-glycolide) Nanoparticles Surface Modification via a Layer-by-Layer Method

Problem Statement
While the layer-by-layer (LbL) adsorption of oppositely charged polyelectrolytes is a recognized strategy for creating multifunctional drug delivery systems based on biodegradable polyesters like poly(D,L-lactide-co-glycolide) (PLGA), the specific influence of modification parameters on the physicochemical properties of nanosized PLGA particles remains insufficiently studied. A critical challenge identified is the stability of PLGA nanoparticles during the initial adsorption of the first polyelectrolyte layer. Although PLGA nanoparticles typically possess a negative electrokinetic potential in aqueous media, the addition of salts (often required for polyelectrolyte solutions) can induce aggregation, particularly in particles lacking steric stabilization. Furthermore, there is a lack of systematic data regarding how the concentration of polyelectrolytes, their molecular weight, and the use of polypeptides versus synthetic polymers affect the final hydrodynamic diameter, polydispersity index (PDI), and zeta potential of the modified nanoparticles. Maintaining particle size below 500 nm is essential for medical applications, necessitating a modification protocol that prevents interparticle flocculation while avoiding excessive size growth.

Methodology
The study utilized PLGA nanoparticles (75/25 mol% lactide/glycolide ratio) synthesized via ring-opening polymerization and prepared by nanoprecipitation. Two primary template types were generated:

Uncoated PLGA NPs: Prepared without any stabilizing agent.
PVA-stabilized PLGA NPs: Prepared with poly(vinyl alcohol) (PVA) and subsequently purified via ultracentrifugation to remove free PVA.

The LbL modification was performed by alternating the adsorption of oppositely charged polyelectrolytes. The experimental design investigated three specific variables:

Preliminary Stabilization: Comparing the LbL modification success on uncoated versus PVA-stabilized templates using the polycation diethylaminoethyldextran (DEAED).
Polyelectrolyte Concentration: Varying the weight ratio of PVA-stabilized PLGA NPs to DEAED (2:1, 1:1, and 1:2) to determine the effect of polycation excess on particle characteristics.
Polyelectrolyte Molecular Weight: Coating PLGA/DEAED particles with sodium dextran sulfate (Na-DS) of two different molecular weights (5 kDa and 500 kDa) to assess the impact of chain length on layer thickness and stability.
Polymer Type: A comparative study using a combination of the synthetic polycation polyethyleneimine (PEI) and the polypeptide sodium salt of poly(L-glutamic) acid (PGA) to evaluate the formation of multilayer structures.

Characterization was conducted using Dynamic Light Scattering (DLS) for hydrodynamic diameter ( $D_h$ ) and polydispersity index (PDI), and Electrophoretic Light Scattering (EPLS) for electrokinetic potential ( $\zeta$ -potential).

Key Results

Necessity of Steric Stabilization: Preliminary steric stabilization with PVA was found to be a prerequisite for successful LbL modification. Uncoated PLGA nanoparticles aggregated significantly upon the addition of the DEAED solution (containing 0.2 M NaCl), resulting in a large increase in $D_h$ (from ~160 nm to ~560 nm) and high polydispersity (PDI 0.32 ± 0.05). In contrast, PVA-stabilized particles successfully underwent charge reversal upon DEAED adsorption. While the PDI value increased from 0.04 ± 0.02 to 0.09 ± 0.02 (a 2.25-fold increase), the particles maintained a narrow size distribution ( $D_h \approx 220$ nm) compared to the uncoated counterparts. The PVA layer provided steric repulsion that prevented aggregation despite the compression of the electrical double layer caused by the salt.
Effect of Polycation Concentration: Varying the weight ratio of PLGA NPs to DEAED (2:1, 1:1, 1:2) did not significantly alter the $D_h$ , PDI, or $\zeta$ -potential of the modified particles. In all cases, the polycation was in excess relative to the theoretical monolayer requirement, leading to surface saturation. Consequently, the $\zeta$ -potential plateaued, indicating that the surface coverage was complete regardless of the specific ratio within the tested range.
Effect of Polyanion Molecular Weight: The molecular weight of the polyanion (Na-DS) significantly influenced the final particle properties. Adsorption of high molecular weight Na-DS (500 kDa) resulted in a larger hydrodynamic diameter (~400 nm) compared to low molecular weight Na-DS (5 kDa). The authors attribute the larger size of the Na-DS500 particles to the formation of a looser, more swollen layer containing more trapped counterions, rather than "bridging" flocculation, as evidenced by the low PDI (0.11) and high absolute $\zeta$ -potential (-48 mV). Conversely, Na-DS5 formed a denser layer with a smaller size increase but a lower absolute $\zeta$ -potential (-26 mV).
Polypeptide vs. Synthetic Polymer: The combination of synthetic PEI and polypeptide PGA allowed for the construction of multilayer structures. The adsorption of PEI increased particle size by ~~40 nm per layer, while PGA adsorption resulted in a smaller increase (~~10 nm). This difference was attributed to the reorganization and conformational changes of the PGA polypeptide chains on the surface. The sequential adsorption of PEI and PGA maintained a low PDI (< 0.3) and kept the final particle size within the preferred range for biomedical applications.

Significance and Claims
The paper claims to provide a systematic study of LbL modification parameters specifically for nanosized PLGA particles, addressing a gap in the literature where such parameters are often insufficiently characterized. The primary contribution is the demonstration that preliminary steric stabilization (e.g., with PVA) is essential for the successful LbL modification of PLGA nanoparticles in saline conditions, preventing the aggregation that occurs with uncoated templates.

The study establishes that:

Once steric stabilization is ensured, the exact weight ratio of polycation to nanoparticles (within an excess range) does not critically alter the final particle size or charge, as the surface saturates.
The molecular weight of the polyelectrolyte is a critical tuning parameter; high molecular weight polymers can create thicker, looser layers with higher surface charge density but significantly larger overall particle sizes, which may limit their biomedical utility if the 500 nm threshold is exceeded.
The combination of synthetic polyelectrolytes and polypeptides (PEI/PGA) offers a viable strategy for building multilayer nanoscale structures without drastically increasing polydispersity or particle size, supporting the potential for creating multifunctional carriers for targeted delivery.

The authors conclude that these findings are crucial for the rational design of PLGA-based delivery systems, ensuring that the modification process yields stable, monodisperse nanoparticles suitable for in vivo applications.

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