Hierarchical self-assembly (HAS) is ap owerful approach to create supramolecular nanostructures for biomedical applications.T his potency,h owever,i sg enerally challenged by the difficulty of controlling the HAS of biomacromolecules and the functionality of resulted HAS nanostructures.H erein, we report am odular approachf or controlling the HAS of discrete metal-organic cages (MOC) into supramolecular nanoparticles,a nd its potential for intracellular protein delivery and cell-fate specification. The hierarchical coordination-driven self-assembly of adamantane-functionalized M 12 L 24 MOC (Ada-MOC) and the hostguest interaction of Ada-MOC with b-cyclodextrin-conjugated polyethylenimine (PEI-bCD) affords upramolecular nanoparticles in ac ontrollable manner.H AS maintains high efficiency and orthogonality in the presence of protein, enabling the encapsulation of protein into the nanoparticles for intracellular protein delivery for therapeutic application and CRISPR/Cas9 genome editing.
Recent innovations in genome editing have enabled the precise manipulation of the genetic information of mammalians, and benefitted the development of next‐generation gene therapy. Despite these advances, several barriers to the clinical translation of genome editing remain, including the intracellular delivery of genome editing machinery, and the risk of off‐target editing effect. Here, we review the recent advance of spatiotemporal delivery of CRISPR/Cas9 genome editing machinery, which is composed of programmable Cas9 nuclease and a single‐guide RNA (sgRNA) using stimuli‐responsive nanoparticles. We discuss the specific chemistries that have been used for controlled Cas9/sgRNA delivery and intracellular release in the presence of endogenous or external signals. These methodologies can leverage biological signals found locally within disease cells, or exogenous signals administrated with spatiotemporal control, through which an improved genome editing could be achieved. We also discuss the future in exploiting these approaches for fundamental biomedical applications and therapeutic genome editing.
Ferroptosis is a new form of regulated, nonapoptotic cell death driven by iron-dependent phospholipid peroxidation. Its therapeutic potential is however, greatly limited by the low efficiency of regulating cell ferroptosis in vivo. Herein, we report a PROTAC-based protein degrader that depletes endogenous glutathione peroxidase 4 (GPX4) and induces cancer cell ferroptosis. We demonstrate that a rationally designed GPX4 degrader, dGPX4, can deplete tumor cell GPX4 via proteasomal protein degradation, showing a five-fold enhancement of ferroptosis induction efficiency compared to that of GPX4 inhibition using ML162. Moreover, we show that the intracellular delivery of dGPX4 using biodegradable lipid nanoparticles (
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