Polypeptoid Synthesis and Applications in Drug Delivery

Polypeptoids are a class of synthetic polymers derived from N-substituted glycine monomers that combine the biocompatibility of peptides with the robust physicochemical properties of synthetic macromolecules. They are typically prepared by controlled ring-opening polymerisation of N-carboxyanhydrides (NCAs) or N-substituted glycine NCAs under conditions that afford precise control over chain length, dispersity and end-group functionality. Advances in initiator design and orthogonal protecting-group strategies have enabled access to sophisticated architectures such as block copolymers, miktoarm stars and core-cross-linked assemblies. In drug delivery, polypeptoids and related copolymers exploit stealth-like behaviour, minimal protein adsorption and stimuli-responsive cargo release. Self-assembled structures—including micelles, worm-like micelles and polymersomes—serve as versatile carriers for small molecules, nucleic acids and biologics. Emerging manufacturing approaches, notably continuous-flow microfluidics, have accelerated scale-up and reproducibility, paving the way for clinical translation. Collectively, the development of well-defined polypeptoid materials is transforming nanomedicine by uniting precise synthetic control with tailored biological performance.

Research from Nature Portfolio

Recent studies have revisited the self-assembly behaviour of amphiphilic block copolypeptoids bearing aromatic and aliphatic side chains. Systematic variation of block composition and assembly protocols revealed a spectrum of morphologies—spherical polymersomes, worm-like micelles and multilayered aggregates—providing a foundation for optimising cargo loading, membrane permeability and in vivo stability.

Another seminal contribution introduced near-infrared fluorescence correlation spectroscopy for direct, real-time characterisation of drug nanocarriers in flowing blood. By labelling carriers or payloads with near-infrared dyes and applying analytical models that account for cellular obstruction, this approach quantifies size, loading efficiency and stability under physiologically relevant conditions, thereby informing the rational design of long-circulating delivery systems.

Polypeptoid Synthesis and Applications in Drug Delivery publication trend

The graph below shows the total number of articles in polypeptoid synthesis and applications in drug delivery across all publications each year (not limited to Nature Index journals).

Technical terms

Polypeptoid: Polymer composed of N-substituted glycine repeat units, analogous to peptides but with side chains on the backbone nitrogen.

N-Carboxyanhydride (NCA): Cyclic monomer used in ring-opening polymerisation to produce polypeptides and polypeptoids with controlled architecture.

Ring-opening polymerisation (ROP): Polymerisation mechanism in which cyclic monomers open and link to form linear or branched polymers under controlled conditions.

Polysarcosine: Poly(N-methyl glycine) polypeptoid renowned for its hydrophilicity, stealth behaviour and minimal protein adsorption in biological media.

Core-cross-linked polymeric micelle (CCPM): Self-assembled nanoparticle whose hydrophobic core is covalently stabilised to enhance structural integrity and control cargo release.

Fluorescence correlation spectroscopy (FCS): Optical technique that analyses fluctuations in fluorescence intensity to determine particle size, concentration and dynamics at the single-molecule level.

Miktoarm star polymer: Polymer architecture featuring three or more arms of differing composition radiating from a central core, enabling complex self-assembly behaviour.

References

1. Polypept(o)ides – Origins, synthesis, applications and future directions. Progress in Polymer Science (2024).
2. Self-Assembly of Amphiphilic Block Copolypeptoids – Micelles, Worms and Polymersomes. Scientific Reports (2016).
3. Monitoring drug nanocarriers in human blood by near-infrared fluorescence correlation spectroscopy. Nature Communications (2018).
4. Complex Structures Made Simple – Continuous Flow Production of Core Cross‐Linked Polymeric Micelles for Paclitaxel Pro‐Drug‐Delivery. Advanced Materials (2023).
5. Polysarcosine-based lipid formulations for intracranial delivery of mRNA. Journal of Controlled Release (2023).