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Biphenyl-capped phosphopeptides instruct cell aggregation into spheroids, with minimal effective concentrations below 10 μM. Key factors driving morphogenesis include the self-assembly ability and dynamic shapeshifting of the peptide assemblies. 

Abstract Rapid cellular uptake of synthetic molecules remains a challenge, and the motif frequently employed to generate prodrugs, succinic ester, unfortunately lowers the efficacy of the desired drugs due to their slow ester hydrolysis and low cell entry. Here we show that succinic ester‐containing diglycine drastically boosts the cellular uptake of supramolecular assemblies or prodrugs. Specifically, autohydrolysis of the diglycine‐activated succinic esters turns the nanofibers of the conjugates of succinic ester and self‐assembling motif into nanoparticles for fast cellular uptake. The autohydrolysis of diglycine‐activated succinic esters and drug conjugates also restores the efficacy of the drugs. 2D nuclear magnetic resonance (NMR) suggests that a “U‐turn” of diglycine favors intramolecular hydrolysis of diglycine‐activated succinic esters to promote autohydrolysis. As an example of rapid autohydrolysis of diglycine‐activated succinic esters for instant cellular uptake, this work illustrates a nonenzymatic bond cleavage approach to develop effective therapeutics for intracellular targeting. 

Enzymatic noncovalent synthesis enables the spatiotemporal control of multimolecular crowding in cells, thus offering a unique opportunity for modulating cellular functions. This article introduces some representative enzymes and molecular building blocks for generating peptide assemblies as multimolecular crowding in cells, highlights the relevant biomedical applications, such as anticancer therapy, molecular imaging, trafficking proteins, genetic engineering, artificial intracellular filaments, cell morphogenesis, and antibacterial, and briefly discusses the promises of ENS as a multistep molecular process in biology and medicine. 

Enzyme-instructed self-assembly (EISA) and hydrogelation is a versatile approach for generating soft materials. Most of the substrates for alkaline phosphatase catalysed EISA utilize phosphotyrosine ( p Tyr) as the enzymatic trigger for EISA and hydrogelation. Here we show the first example of phosphonaphthyl ( p NP) and phosphobiphenyl ( p BP) motifs acting as faster enzymatic triggers than phosphotyrosine for EISA and hydrogelation. This work illustrates novel enzyme triggers for rapid enzymatic self-assembly and hydrogelation.