Precision Sequence‐Defined Polymers: From Sequencing to Biological Functions

Abstract

Precise sequence‐defined polymers (SDPs) with uniform chain‐to‐chain structure including chain length, unit sequence and end functionalities, represent the pinnacle of sophistication in the realm of polymer science. For example, the absolute control over the unit sequence of SDPs allows for bottom‐up design of polymers with hierarchical microstructures and functions. Accompanied with the development of synthetic techniques towards precision SDPs, the decoding of SDP sequences and construction of advanced functions irreplaceable with other synthetic materials is of central importance. In this Minireview, we focus on recent advances in SDP sequencing techniques including tandem mass spectrometry (MS), chemically assisted primary MS, as well as other non‐destructive sequencing methods such as nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD), and nanopore sequencing. Additionally, we delve into the promising prospects of SDP functions in the area of cutting‐edge biological research. Topics of exploration include gene delivery systems, the development of hybrid materials combining SDPs and nucleic acids, protein recognition and regulation, as well as the interplay between chirality and biological functions. A brief outlook towards the future directions of SDPs is also presented.

Advanced Smart Biomaterials for Regenerative Medicine and Drug Delivery Based on Phosphoramidite Chemistry: From Oligonucleotides to Precision Polymers

“…In recent years, nanomaterial-based drug/gene delivery systems have shown great therapeutic potential in biomedical applications. The design elements, including molecular size, number of charges, sequences, and topologies, would dramatically influence the delivery efficiency and therapeutic effects, 103 while the precise control on molecular structure of SDPs could assist the construction of more challenging and sophisticated delivery vehicles. 104 As mentioned in section 3.2, Liu and co-workers proposed the frame-guided assembly strategy to prepare the vesicles with customized size and morphology, which could be further utilized in effective delivery and controlled release of various therapeutic drug molecules.…”

Recent Advances in Stimuli-Responsive Self-Immolative Polymers for Drug Delivery and Molecular Imaging

“…There are not many methods that can successfully sequence synthetic polymers, including nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD), nanopore, and some mass spectrometry (MS)-based methods. 76 Nondestructive techniques like NMR and CD are difficult to fully accomplish sequence determination in polymers with complex sequences and long chains due to the stacking and deviation of peaks. 77 MS-based methods require stringent sample prerequisites because the random dissociation of backbone and side chains results in complex and noisy MS signals.…”

“…183 Sequence-defined polymers have precise molecular weights and clear molecular structures, making them unique in complex systems and promising for innovations in molecular imaging and other fields. 76 Liu et al 81 prepared four types of digital micelles using a set of sequencedefined amphiphilic SIPs, each with either rod-like nanostructures with different lengths or spherical morphology. In MALDI-TOF MS analysis, different sequence structures resulted in distinct intervals between mass spectrometric peaks, allowing for the differentiation and quantification of signals corresponding to each polymer.…”

“…Most synthetic polymers cannot undergo sequential cleavage reactions similar to Edman degradation, which prevents them from being resolved in this way. There are not many methods that can successfully sequence synthetic polymers, including nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD), nanopore, and some mass spectrometry (MS)-based methods . Nondestructive techniques like NMR and CD are difficult to fully accomplish sequence determination in polymers with complex sequences and long chains due to the stacking and deviation of peaks .…”

“…As mentioned in Section 2.3, with the advancement of synthesis and detection methods for sequence-defined polymers, researchers have been able to rapidly prepare sequence-defined SIPs . Sequence-defined polymers have precise molecular weights and clear molecular structures, making them unique in complex systems and promising for innovations in molecular imaging and other fields . Liu et al prepared four types of digital micelles using a set of sequence-defined amphiphilic SIPs, each with either rod-like nanostructures with different lengths or spherical morphology.…”