From biting to engulfment: curvature-actin coupling controls phagocytosis of soft, deformable targets

Phagocytosis is a fundamental process of the innate immune system, yet the physical determinants that govern the engulfment of soft, deformable targets remain poorly understood. Existing theoretical models typically approximate targets as rigid particles, overlooking the fact that both immune cells and many biological targets undergo significant membrane deformation during contact. Here, we develop a Monte Carlo-based membrane simulation framework to model the interactions of multiple vesicles, enabling us to explore phagocytosis-like processes in systems where both the phagocyte and the target possess flexible, thermally fluctuating membranes. We first validate our approach against established observations for the engulfment of rigid objects. We then investigate how the mechanical properties of a soft target – specifically membrane bending rigidity govern the outcome of phagocytic interactions. Our simulations reveal three distinct mechanical regimes: (i) biting or trogocytosis, in which the phagocyte extracts a portion of the target vesicle; (ii) pushing, where the target is displaced rather than engulfed; and (iii) full engulfment, in which the target is completely internalized. Increasing membrane tension via internal pressure produces analogous transitions, demonstrating a unified mechanical origin for these behaviours. Qualitative comparison with experiments involving Giant Unilamellar Vesicles (GUVs, deformable microparticles) and lymphoma cells supports the relevance of these regimes to biological phagocytosis. Together, these results highlight how target deformability fundamentally shapes phagocytic success and suggest that immune cells may exploit mechanical cues to recognize among different classes of soft targets.

💡 Research Summary

In this paper the authors address a long‑standing gap in our understanding of how phagocytes deal with soft, deformable targets. Traditional theoretical treatments have treated targets as rigid spheres, ignoring the fact that both immune cells and many physiological targets undergo substantial membrane deformation during contact. To overcome this limitation the authors develop a Monte‑Carlo (MC) based three‑dimensional membrane model that can simulate two interacting vesicles, each represented by a triangulated mesh of vertices and edges. The model incorporates (i) a short‑range adhesion energy (‑E_ad) between nearby vertices, (ii) curved‑membrane protein complexes (CMCs) that possess an intrinsic curvature and a pairwise binding energy, and (iii) active protrusive forces (F) applied at CMC sites to mimic actin polymerization. By adjusting the bending rigidity (κ) of the target vesicle and the internal osmotic pressure (which changes membrane tension), the authors explore a broad mechanical parameter space.

First, they validate the framework against known analytical results for the adhesion of two bare vesicles and for a vesicle adhering to a rigid sphere, confirming that contact angles and energy minima match theory. Introducing CMCs leads to larger contact areas and, above a critical adhesion strength, a spontaneous symmetry‑breaking where one vesicle forms a cup‑shaped protrusion that partially wraps the other. This transition is driven by a net reduction in total energy: the gain in adhesion energy outweighs the cost of increased bending energy in the cup.

The core of the study focuses on a “cell‑like” vesicle (≈3 000 vertices) interacting with a smaller “target” vesicle (≈800 vertices). The target’s bending rigidity κ is varied from very soft (20 k_BT) to effectively rigid (2 000 k_BT). When CMCs are passive (F = 0) the cell‑like vesicle can eventually engulf targets of any rigidity, but softer targets are engulfed faster because they deform, allowing the cell to cover a smaller cross‑section. When CMCs are active (F > 0) three distinct dynamical regimes emerge as κ changes:

1. Biting (trogocytosis) – For low κ the target deforms dramatically; the cell extracts a membrane “finger” that pulls off a piece of the target.
2. Pushing – At intermediate κ the cell forms a suction‑cup‑like contact that stalls and then retracts, ultimately pushing the target away.
3. Engulfment – For high κ the target behaves like a rigid sphere and is fully internalized.

A comparable set of transitions is observed when membrane tension is increased via internal pressure, demonstrating that both bending rigidity and tension act as unified mechanical controls.

Finally, the authors compare their simulation outcomes with experiments using giant unilamellar vesicles (GUVs) and lymphoma cells. The three regimes identified in silico—partial biting of soft GUVs, pushing of intermediate‑stiffness particles, and complete engulfment of stiff cancer cells—are recapitulated experimentally, supporting the model’s relevance.

Overall, the study provides a mechanistic, physics‑based framework that links membrane curvature‑actin coupling, target rigidity, and membrane tension to the fate of phagocytic encounters. It suggests that immune cells may read out mechanical cues to decide whether to bite, push, or fully engulf a target, offering new perspectives for immunotherapy design and the engineering of synthetic particles that can evade or trigger phagocytosis.