To transform common low-molecular-weight (LMW) cationic polymers, such as polyethylenimine (PEI), to highly efficient gene vectors would be of great significance but remains challenging. Because LMW cationic polymers perform far less efficiently than their high-molecular-weight counterparts, mainly due to weaker nucleic acid encapsulation, herein we report the design and synthesis of a dipicolylamine-based disulfide-containing zinc(II) coordinative module (Zn-DDAC), which is used to functionalize LMW PEI (M ≈ 1800 Da) to give a non-viral vector (Zn-PD) with high efficiency and safety in primary and stem cells. Given its high phosphate binding affinity, Zn-DDAC can significantly promote the DNA packaging functionality of PEI and improve the cellular uptake of formulated polyplexes, which is particularly critical for hard-to-transfect cell types. Furthermore, Zn-PD polymer can be cleaved by glutathione in cytoplasm to facilitate DNA release post internalization and diminish the cytotoxicity. Consequently, the optimal Zn-PD mediates 1-2 orders of magnitude higher gluciferase activity than commercial transfection reagents, Xfect and PEI, across diverse cell types, including primary and stem cells. Our findings provide a valuable insight into the exploitation of LMW cationic polymers for gene delivery and demonstrate great promise for the development of next-generation non-viral vectors for clinically viable gene therapy.

Graphene has recently emerged as an important and exciting material. Inspired by its outstanding properties, many researchers have extensively studied graphene-related materials both experimentally and theoretically. Porous graphene is a collection of graphene-related materials with nanopores in the plane. Porous graphene exhibits properties distinct from those of graphene, and it has widespread potential applications in various fields such as gas separation, hydrogen storage, DNA sequencing, and supercapacitors. In this review, we summarize recent progress in studies of the properties, preparation, and potential applications of porous graphene, and show that porous graphene is a promising material with great potential for future development.graphene, porous graphene, electronic structure, gas separation, DNA sequencing Citation:Xu P T, Yang J X, Wang K S, et al. [9] have made the preparation of large-area graphene feasible. The most intriguing aspect of graphene is its extraordinary properties. Graphene, which is constructed by strong sp 2 covalent bonds, is believed to be the strongest material ever measured [10]. Experiments have revealed that graphene exhibits a high ambipolar electric-field effect at room temperature, better conductivity than any other known material [3], and many other novel properties, including room-temperature quantum Hall effects, mass-less Dirac electrons near the K point, and high mobility of carriers (10 6 m s −1 , close to the speed of light) [11][12][13]. All these properties distinguish graphene from ordinary materials, and make graphene an ideal candidate for the manufacture of electronic devices. To develop a full understanding of its nature and realize the full potential of graphene, extensive investigations have proceeded in various directions. For instance, the electronic and magnetic properties of graphene can be modified by hydrogenation [14] and doping [15]. Another research area, porous graphene, has also attracted increasing attention recently. Porous graphene is a collection of graphene-related materials with nanopores in the plane. Depending on the production techniques used, the pore size ranges from atomic precision to nanoscale. As a result of the nanopores in the graphene plane, porous graphene exhibits properties distinct from those of pristine graphene, leading to its potential applications in numerous

Natural polycations, such as poly(l-lysine) (PLL) and chitosan (CS), have inherent superiority as non-viral vectors due to their unparalleled biocompatibility and biodegradability. However, the application was constrained by poor transfection efficiency and safety concerns. Since previous modification strategies greatly weakened the inherent advantages of natural polycations, developing a strategy for functional group introduction with broad applicability to enhance the transfection efficiency of natural polycations without compromising their cationic properties is imperative. Herein, two uncharged functional diblock oligomers P(DMAEL-b-NIPAM) and P(DMAEL-b-Vlm) were prepared from a lactose derivative, N-iso-propyl acrylamide (NIPAM) as well as 1-vinylimidazole (Vlm) and further functionalized with four small ligands folate, glutathione, cysteine and arginine, respectively, aiming to enhance the interactions of complexes with cells, which were quantified utilizing a quartz crystal microbalance (QCM) biosensor, circumventing the tedious material screening process of cell transfection. Upon incorporation with PLL and DNA, the multifunctional oligomers endow the formulated ternary complexes with great properties suitable for transfection, such as anti-aggregation in serum, destabilized endosome membrane, numerous functional sites for promoted endocytosis and therefore robust transfection activity. Furthermore, different from the conventional strategy of decreasing cytotoxicity by reducing the charge density, the multifunctional oligomer incorporation strategy maintains the highly positive charge density, which is essential for efficient cellular uptake. This system develops a new platform to modify natural polycations towards clinical gene therapy.

Amines have been extensively involved in vector design thus far, however, their clinical translation has been impeded by several obstacles: cytotoxicity, polyplex serum instability and low efficacy in vivo. In pursuit of functional groups to substitute amines in vector design to address these disadvantages is of great significance. Herein, we report well-tailored noncationic copolymers that contain hydrophilic, hydrophobic, and zinc coordinative moieties through reversible addition–fragmentation chain transfer (RAFT) polymerization for efficient and safe gene delivery. These polymers are capable of condensing DNA, enabling the formation of uncharged polyplexes. Especially, the zinc coordinative ligand can simultaneously benefit strong DNA binding, robust cellular uptake, efficacious endosomal destabilization, low cytotoxicity, and avoidance of serum protein adsorption. The coordinative module holds great promise to substitute amines and inspires the development of next-generation gene vectors. More importantly, the coordinative copolymers illuminate the possibility and potential of noncationic gene delivery systems for clinical applications.

Virus-inspired mimics for gene therapy have attracted increasing attention because viral vectors show robust efficacy owing to the highly infectious nature and efficient endosomal escape. Nonetheless, until now, synthetic materials have failed to achieve high "infectivity," and especially, the mimicking of virus spikes for "infection" is underappreciated. Herein, a virus spike mimic by a zinc (Zn) coordinative ligand that shows high affinity toward phosphate-rich cell membranes is reported. Surprisingly, this ligand also demonstrates superior functionality of destabilizing endosomes. Therefore, the Zn coordination is more likely to imitate the virus nature with high cell binding and endosomal membrane disruption. Following this, the Zn coordinative ligand is functionalized on a bioreducible cross-linked peptide with alkylation that imitates the viral lipoprotein shell. The ultimate virus-mimicking nanoparticle closely imitates the structures and functions of viruses, leading to robust transfection efficiency both in vitro and in vivo. More importantly, apart from targeting ligand- and cell-penetrating peptide, the metal coordinative ligand may provide another option to functionalize diverse biomaterials for enhanced efficacy, demonstrating its broad referential significance to pursue nonviral vectors with high performance.

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(HEMA-b-NIPAM) was incorporated into PEI/P(HEMA-b-NIPAM)/pDNA ternary complexes through non-electrostatic assembly to enhance the interaction between complexes and cellular/endocellular membranes to improve gene transfection.