Cargo-selective and adaptive delivery of nucleic acid therapeutics by bola-amphiphilic dendrimers.

Nucleic acid therapeutics are becoming an important drug modality, offering the unique opportunity to address "undruggable" targets, respond rapidly to evolving pathogens, and treat diseases at the gene level for precision medicine. However, nucleic acid therapeutics have poor bioavailability and are chemolabile and enzymolabile, imposing the need for delivery vectors. Dendrimers, by virtue of their well-defined structure and cooperative multivalence, represent precision delivery systems. We synthesized and studied bola-amphiphilic dendrimers for cargo-selective and on-demand delivery of DNA and small interfering RNA (siRNA), both important nucleic acid therapeutics. Remarkably, superior performances were achieved for siRNA delivery with the second-generation dendrimer, yet for DNA delivery with the third generation. We systematically studied these dendrimers with regard to cargo binding, cellular uptake, endosomal release, and in vivo delivery. Differences in size both of the dendrimers and their nucleic acid cargos impacted the cooperative multivalent interactions for cargo binding and release, leading to cargo-adaptive and selective delivery. Moreover, both dendrimers harnessed the advantages of lipid and polymer vectors, while offering nanotechnology-based tumor targeting and redox-responsive cargo release. Notably, they allowed tumor- and cancer cell-specific delivery of siRNA and DNA therapeutics for effective treatment in different cancer models, including aggressive and metastatic malignancies, outperforming the currently available vectors. This study provides avenues to engineer tailor-made vectors for nucleic acid delivery and precision medicine.

Self-assembly of amphiphilic phospholipid peptide dendrimer-based nanovectors for effective delivery of siRNA therapeutics in prostate cancer therapy.

RNA interference (RNAi) holds great promise for therapeutic applications. However, safe and successful clinical translation essentially requires further advancement of developing efficient delivery systems. Herein, we report that amphiphilic phospholipid peptide dendrimers (AmPPDs) could mediated effective delivery of siRNA targeting Hsp27 for treating castration-resistant prostate cancer (CRPC). AmPPDs bears natural lipid derivative DSPE as the hydrophobic tail and different dendritic l-lysine as the hydrophilic head, capable of compacting siRNA into nanoparticles to protect it from enzymatic degradation. Interestingly, DSPE-KK2, AmPPD bearing smaller hydrophilic dendron, promoting more efficient intracellular uptake and endosome release of the so-formed siRNA complexes, as well as better siRNA releasing ability, ultimately resulting in more potent gene silencing and anticancer effects both in vitro and in vivo. Such outstanding performance of DSPE-KK2 in siRNA delivery may attribute to its optimal balance between the hydrophobic tail and hydrophilic dendritic portion. Our findings provide guidance for the development of safe and effective dendrimer-based siRNA delivery system, thus bringing new hope for combating various diseases.

A supramolecular fluorescent vesicle based on a coordinating aggregation induced emission amphiphile: insight into the role of electrical charge in cancer cell division.

Binding of Zn2+ to the coordinating supramolecular vesicle based on an aggregation induced emission amphiphile TPE-BPA immediately triggers the formation of charged vesicles. This induces vesicle fission and fluorescence reduction, suggesting a looser molecular packing in the charged vesicle membrane. Since cancer cells are highly charged, this indicates that the quick fission of cancer cells may have electrical charge origin.

Off-diagonal Bethe ansatz and exact solution of a topological spin ring.

A general method is proposed for constructing the Bethe ansatz equations of integrable models without U(1) symmetry. As an example, the exact spectrum of the XXZ spin ring with a Möbius-like topological boundary condition is derived by constructing a modified T-Q relation based on the functional connection between the eigenvalues of the transfer matrix and the quantum determinant of the monodromy matrix. With the exact solution, the elementary excitations of the topological XX spin ring are discussed in detail. It is found that the excitation spectrum indeed shows a nontrivial topological nature.