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 Hoopen, Gert Storm, Peter Hoogevest, Wouter K. Otter and Jai Prakash ()
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Praneeth R. Kuninty: TechMed Centre, University of Twente
Karin Binnemars-Postma: TechMed Centre, University of Twente
Ahmed Jarray: University of Twente
Kunal P. Pednekar: TechMed Centre, University of Twente
Marcel A. Heinrich: TechMed Centre, University of Twente
Helen J. Pijffers: TechMed Centre, University of Twente
Hetty Hoopen: TechMed Centre, University of Twente
Gert Storm: TechMed Centre, University of Twente
Peter Hoogevest: Phospholipid Research Centre
Wouter K. Otter: University of Twente
Jai Prakash: TechMed Centre, University of Twente

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32091-9

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