Advances in the Structural Design of Polyelectrolyte Complex Micelles

Abstract

Polyelectrolyte complex micelles (PCMs) are a unique class of self-assembled nanoparticles that form with a core of associated polycations and polyanions, microphase-separated from neutral, hydrophilic coronas in aqueous solution. The hydrated nature and structural and chemical versatility make PCMs an attractive system for delivery and for fundamental polymer physics research. By leveraging block copolymer design with controlled self-assembly, fundamental structure-property relationships can be established to tune the size, morphology, and stability of PCMs precisely in pursuit of tailored nanocarriers, ultimately offering storage, protection, transport, and delivery of active ingredients. This perspective highlights recent advances in predictive PCM design, focusing on (i) structure-property relationships to target specific nanoscale dimensions and shapes and (ii) characterization of PCM dynamics primarily using time-resolved scattering techniques. We present several vignettes from these two emerging areas of PCM research and discuss key opportunities for PCM design to advance precision medicine.

Figure 1

Building blocks and microphase separation process of polyelectrolyte complex micelles (PCMs). For nomenclature, A represents a neutral, hydrophilic block, while B/C represents oppositely charged polyelectrolyte blocks. Typical PCMs consist of an AB diblock polycation and either an AC diblock polyanion or a C homopolyanion.

Figure 2

Aggregated data from published (AB + C) polyelectrolyte complex micelle (PCM) experimental studies using strong polyelectrolytes at stoichiometric charge ratios, overlaid with experimental scaling laws shown as black lines. The data were normalized using scaling laws for two block lengths and plotted against the third block length, collapsing to show scaling for the block length of interest. The available literature provides aggregated data for core size (A–C), hydrodynamic size (D–E), and aggregation number (F). The data represents PCMs from six publications^,,,,, using numerous synthetic and biological polymers and the scaling laws are experimental, consistent with theoretical predictions for PCMs between the star-like and crew-cut regimes. Adapted from Marras et al. Copyright 2021 American Chemical Society.

Figure 3

Dynamics of polyelectrolyte complex micelles (PCMs). (A) Chemical structures of poly(ethylene oxide)-block-poly(vinyl benzyl trimethylammonium chloride) (PEO-b-PVBTMA, boxed in red), sodium poly(acrylate) (PAA, boxed in blue), poly(ethylene oxide)-block-poly(sodium 4-styrenesulfonate) (PEO-b-PSS, boxed in blue), and poly(sodium 4-styrenesulfonate) (PSS, boxed in blue). (B) Illustration of the relevant time and length scales investigated in PCM formation (purple), chain exchange (green), and disassembly (orange), ranging from milliseconds to minutes using small-angle X-ray scattering, cryogenic electron microscopy, and dynamic light scattering.

Figure 4

Time-resolved small-angle X-ray scattering (TR-SAXS) reveals distinct formation pathways of polyelectrolyte complex micelles (PCMs). (A) For PEO-b-PVBTMA/PAA systems, within 100 ms well-defined spherical micelles incrementally grow into larger micellar entities, as denoted by the black arrow. Adapted from Wu et al. Copyright 2020 American Chemical Society. (B) For PEO-b-PVBTMA/PSS systems, within 3 ms aggregates break apart into smaller micellar entities, as denoted by the black arrow. Adapted from Amann et al. Copyright 2019 American Chemical Society.

Figure 5

Chain exchange of polyelectrolyte complex micelles (PCMs) upon formation as a function of electrostatic interactions, nonelectrostatic interactions, and polyelectrolyte length using Langevin dynamics simulations. (A) Histograms of the PCM size distribution varying nonelectrostatic attraction strength between polyelectrolytes at ε_LJ = 0.05k_BT (blue), ε_LJ = 0.15k_BT (red), and ε_LJ = 0.25k_BT (gray); insets show snapshots of the simulated PCMs with N_negative = N_positive = 20 and N_netural = 50. (B) Comparison of the number of chain expulsion/insertion and micelle fission/fusion events for PCMs as a function of polyelectrolyte length ratio (N_negative/N_positive) at increasing nonelectrostatic attraction strengths. Adapted from Bos et al. Copyright 2019 American Chemical Society.