Cancer immune therapy using engineered ‛tail-flipping’ nanoliposomes targeting alternatively activated macrophages

Praneeth R. Kuninty, Karin Binnemars-Postma, Ahmed Jarray, Kunal P. Pednekar, Marcel A. Heinrich, Helen J. Pijffers, Hetty ten Hoopen, Gert Storm, Peter van Hoogevest, Wouter K. den Otter, Jai Prakash*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Alternatively-activated, M2-like tumor-associated macrophages (TAM) strongly contribute to tumor growth, invasiveness and metastasis. Technologies to disable the pro-tumorigenic function of these TAMs are of high interest to immunotherapy research. Here we show that by designing engineered nanoliposomes bio-mimicking peroxidated phospholipids that are recognised and internalised by scavenger receptors, TAMs can be targeted. Incorporation of phospholipids possessing a terminal carboxylate group at the sn-2 position into nanoliposome bilayers drives their uptake by M2 macrophages with high specificity. Molecular dynamics simulation of the lipid bilayer predicts flipping of the sn-2 tail towards the aqueous phase, while molecular docking data indicates interaction of the tail with Scavenger Receptor Class B type 1 (SR-B1). In vivo, the engineered nanoliposomes are distributed specifically to M2-like macrophages and, upon delivery of the STAT6 inhibitor (AS1517499), zoledronic acid or muramyl tripeptide, these cells promote reduction of the premetastatic niche and/or tumor growth. Altogether, we demonstrate the efficiency and versatility of our engineered “tail-flipping” nanoliposomes in a pre-clinical model, which paves the way to their development as cancer immunotherapeutics in humans.

Original languageEnglish
Article number4548
JournalNature communications
Volume13
Issue number1
Early online date4 Aug 2022
DOIs
Publication statusE-pub ahead of print/First online - 4 Aug 2022

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