Mechanistic Insights into Unary Peptide–Membrane Interactions Enable Stable Encapsulation and Trigger-Responsive Peptidyl Liposomes

TL;DR

Researchers uncovered how peptides interact with membranes to create stable, trigger-responsive liposomes for drug delivery.

Contribution

A unified framework for designing stable yet trigger-responsive peptidyl liposomes using the MAG2 AMP backbone.

Findings

MAG2 is the first AMP backbone that allows stable liposome encapsulation without leakage.

Trigger-induced peptide unmasking leads to membrane defect formation and content release.

Hierarchical molecular events were revealed using cryo-EM, SAXS, and fluorescence imaging.

Abstract

Efforts to engineer
trigger-responsive peptidyl liposomes have
historically been limited by premature release following peptide conjugation,
reflecting an incomplete understanding of tethered peptide–membrane
interactions. Here, we establish a unified mechanistic framework for
designing encapsulation-stable yet trigger-responsive liposomes by
elucidating how membrane-anchored peptides interact with membranes.
Screening identified MAG2 as, thus far, the only AMP backbone that
can be surface-masked without liposome leakage while preserving latent
lytic activity-an outcome previously unattainable in unary
peptidyl liposome systems. Cryo-EM/cryo-ET, SAXS, CD, FLIM/fluorescence
imaging, and MTT assays collectively unveil a hierarchical cascade
of molecular events: masked peptide–membrane conjugation with
stable liposome encapsulation, lateral-diffusion-driven outer leaflet
PEG-layer expansion, trigger-induced peptide unmasking, aggregation-mediated
membrane defect formation, and outer leaflet PEG-layer collapse, culminating
in liposomal content release, intracellular distribution, and trigger-induced
cell-killing efficacy. These findings uncover a unary peptide–membrane
interaction mechanism that will redefine the design principles of
trigger-responsive therapeutic peptidyl liposomes.

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