In Situ Construction of Functional Assemblies in Living Cells for Cancer Therapy

Abstract

Peptide-based materials hold great promise for various biomedical applications and have drawn increasing attention over the past five years. Despite the progress in fabrication and handling peptide materials in vitro, manipulating assemblies of peptides in living cells (or animals) is still in its infancy. In this contributing review, recent work is summarized using endogenous triggers to construct functional assemblies of peptides in vivo. After introducing the triggers for inducing peptide assemblies, the recent progress is highlighted of the in situ construction of assemblies for biomedical applications with emphasis on cancer therapy. Finally, a brief perspective is provided to discuss the future promises and challenges of this emerging area of supramolecular chemistry.

Controlling Intracellular Enzymatic Self-Assembly of Peptide by Host–Guest Complexation for Programming Cancer Cell Death

“…Remarkably, enzyme instructed self-assembly, mimicking the most biological processes (e.g., actin dynamics, signalosomes, and granules) in the living systems, is the most efficient strategy to control the kinetics of molecular assemblies. Inspired by the natural enzymatic processes and functional assemblies in living cells, the recent emergent strategy for cancer therapy, which differs from conventional approaches (chemotherapy, immunotherapy, and targeted therapy), is to generate chemical assemblies of small molecules in situ of cancer cells. − A recent remarkable example of such a strategy is to use enzyme-induced self-assembly (EISA) to control cell behavior around or inside cells by an overexpressing enzyme. − More importantly, the formation rate of enzymatic assemblies is the key factor for their cell targeting ability and final bioactivity. However, regulating EISA kinetics with organelle targeting in a simple way for cancer therapy remains challenging.…”

“…23,24 Herein, we report using the host−guest complexation, 25−28 which has been extensively explored in sensing, regulating protein functions, and drug delivery, to modulate the kinetics of EISA assemblies' formation in cancer cells with mitochondria targeting and inducing cancer cell death selectively. To achieve the approach, we designed enzyme responsive peptide with the N-terminal modification of the ferrocenyl group (Figure 1A), which can interact with pillar [6]arene (WP6) to form a pH-sensitive host−guest complex (Figure 1B). The formed complex prevents the enzymatic reaction on the cell surface and promotes cellular uptake of peptides.…”

“…30−32 The triphenylphosphine (TPP) group at the side chain of lysine is used to target the mitochondria matrix of cells. 33 The ferrocenyl group (Fc) serves as a guest motif for a synthetic macrocyclic host 34 of pillar [6]arene (WP6) to form a host−guest complex. Such a design allows us to use the host−guest complexation between the pillar [6]arene host and the Fc guest to control the enzymatic self-assembly of Fc-TPP1.…”

“…33 The ferrocenyl group (Fc) serves as a guest motif for a synthetic macrocyclic host 34 of pillar [6]arene (WP6) to form a host−guest complex. Such a design allows us to use the host−guest complexation between the pillar [6]arene host and the Fc guest to control the enzymatic self-assembly of Fc-TPP1. Since the host−guest complex of Fc-TPP1 and WP6 has the pH-responsive property, 35 the guest molecules could easily escape from the lysosome and are transported into the mitochondria matrix of cancer cells.…”