Aug 2026· Colloids and Surfaces B: Biointerfaces· Vol 268 Pt 2, pp.
116044
· 0 citations· 42 references
Medicine
Abstract
Polyion complex (PIC) vesicles are attractive carriers for mRNA delivery, yet their assembly is often compromised by charged cargos that disrupt the electrostatic interactions required for vesicle formation. Here, we report triblock polyampholyte vesicles (TBPVs) that encode preferential polymer-polymer interactions, enabling robust vesicle assembly independent of cargo-mediated disruption. Constructed from poly(ethylene glycol)-b-poly(L-lysine)-b-poly(aspartic acid) copolymers, TBPVs encapsulate both free mRNA and pre-condensed mRNA polyplexes while preserving vesicle integrity. Notably, the TBPVs encapsulating pre-condensed mRNA polyplexes demonstrated significant protein expression both in vitro and in vivo. Disulfide crosslinking of the vesicular membrane further confers stability under physiological conditions, while providing redox responsiveness for intracellular disassembly and cargo release. Systemically administered SS-TBPVs loaded with mRNA polyplexes enable detectable hepatic transgene expression in vivo. These findings support triblock polyampholyte PIC vesicles as a versatile and cargo-tolerant platform for polyplex-based nucleic acid delivery.
A novel ternary lipopolyplex (LPP) platform of lipid/HBPL/mRNA LPPs by incorporating hyperbranched poly-L-lysine (HBPL) as a functional polymeric core that yields high transfection efficiency across multiple cell lines, significantly enhanced dendritic cell (DC) maturation, and superior biocompatibility over a commercial transfection reagent.
Huidi Meng, Bingjie Fu, Min Liang et al.· Advanced Healthcare Material...· 0 citations
Tuning polycation chain length with core π-π interactions is key to unlocking highly efficient mRNA delivery in micelles, and achieves 2-fold higher protein expression in vivo compared to shorter or longer chain variants.
Yuki Nakashima, Pengwen Chen, Guanghao Hu et al.· Biomaterials Science· 0 citations
This Perspective revisits cationic polymer-lipid nanoparticles not as historical precursors to ionizable lipid LNPs, but as a macromolecular materials space that can clarify and extend current RNA delivery design.
Vesicles formed from amphiphilic copolymers, alone or blended with phospholipids, offer superior mechanical and chemical stability compared to conventional lipid vesicles. This makes them an attractive chassis, one that can be further developed and expanded to enable specific applications, such as drug delivery, diagnostic biosensing, construction of artificial cells, and bioinspired micro- and nanoreactors. In particular, functionalization through membrane protein incorporation is essential for many of these applications. Here, we present a protocol for preparing membrane protein-functionalized large unilamellar vesicles (LUVs) from the graft copolymer PDMS-g-PEO via detergent-mediated reconstitution. Furthermore, we describe how these large vesicles can be converted to giant unilamellar vesicles (GUVs) using a fusion-electroformation approach. The protocol covers fluorescence labeling of membrane proteins, preparation of polymer and hybrid LUVs, membrane protein reconstitution, size distribution analysis via dynamic light scattering (DLS), assessment of protein activity via oxygen consumption measurements, preparation of protein-functionalized GUVs, and analysis of protein insertion and proton pumping activity in GUVs via confocal microscopy. Representative results demonstrate the formation of monodisperse proteo-LUVs with a polydispersity index (PDI) below 0.2, and successful generation of proteo-GUVs ranging from 5-35 µm in diameter. Protein activity is confirmed by oxygen consumption measurements in both polymer LUVs (18.2 nmol/min/mL) and hybrid LUVs (26.9 nmol/min/mL). Protein insertion into GUVs is quantified via fluorescence intensity, yielding 20.6 ± 3.7 a.u. for polymer GUVs and 26.2 ± 5.0 a.u. for hybrid GUVs. Proton pumping activity in GUVs, monitored via an encapsulated pH-sensitive dye, is consistent with protein functionality, with inward proton pumping being predominant. The copolymer's mechanical softness and lipid-like bilayer thickness (~5.3 nm) support efficient protein insertion and preservation of functionality.
Nika Otrin, Chee Seng Man, Wenqi Huang et al.· Journal of Visualized Experi...· 0 citations
Polythioctic acid (PTA) and its derivatives carrying disulfide bonds within the polymer backbone have emerged as leading candidates for yielding degradable and recyclable polymers. However, their development has been impeded by the persistent trade-off between degradability and mechanical strength, as well as the lack of effective polymerization strategies that can be used under mild conditions. Herein, we report a polyoxometalate (POM)-mediated "one-stone-three-birds" strategy, in which rapid ring-opening polymerization (ROP) of TA is synchronously coupled with noncovalent crosslinking under mild ambient conditions. Combined experimental and theoretical investigations reveal that POM nanoclusters act as multifunctional "stones": oxidizing TA to generate cationic radical species that initiate ROP, engaging in strong electrostatic interactions with the sulfonium termini of the resulting PTA chains to form robust polymer networks with high adhesion strength (>11 MPa), and imparting a redox-responsive colorimetric signal. This synergistic integration of mechanical reinforcement and chromic response provides a new strategy for designing adhesives with coupled structural integrity and optical feedback, which enables in situ visual indication of material changes during leakage of oxidizing species in confined environments.
Jun Fang, Xiao Xiao, Pengyuan Ye et al.· Angewandte Chemie· 0 citations
Here, we report phospholipid-mimetic cationic copolymers that facilitate intracellular oligonucleotide delivery at a net charge-neutral polymer/DNA mixing ratio. Conventional nucleic acid delivery nanocarriers are mainly internalized through endocytosis, which often leads to endosomal sequestration and nucleic acid degradation, thereby reducing delivery efficiency and therapeutic efficacy. To address these issues, we developed a cationic phospholipid-mimetic random copolymer designed to physically form polyion complexes with anionic oligomeric DNA. Instead of simply maximizing cationic charge, our approach utilizes the membrane-interactive interfacial amphiphilicity of copolymer/oligonucleotide polyion complexes alongside hydrophobic monomer unit-mediated interactions to regulate interactions with cellular membranes. Consequently, at a net charge-neutral mixing ratio of the cationic polymer and anionic DNA, the polyion complexes showed reduced LysoTracker colocalization, uptake that was partially retained under ATP-depleted and endocytosis-inhibited conditions, and exhibited minimal cytotoxicity and negligible plasma membrane damage in vitro. Functionally, this system enabled antisense oligonucleotide delivery, reducing Bcl-2 mRNA expression by 57% relative to untreated cells in HepG2 cells. These findings suggest that interfacial regulation through phospholipid-mimetic amphiphilic polyion complexes can facilitate intracellular oligonucleotide delivery under net charge-neutral conditions, with uptake showing reduced sensitivity to suppression of classical energy-dependent endocytosis while maintaining negligible plasma membrane damage.
Fanlu Meng, Tatsuro Goda· Langmuir· 0 citations
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