🔬 condensed matter

From biting to engulfment: Target mechanics determines modes of phagocytosis through curvature--actin coupling

By integrating theoretical modeling with experimental validation, this study demonstrates that target stiffness governs distinct phagocytic outcomes—ranging from biting and pushing to complete engulfment—through a curvature-actin coupling mechanism.

Original authors: Shubhadeep Sadhukhan, Caitlin E. Cornell, Mansehaj Kaur Sandhu, Marta Batet Palau, Youri Peeters, Stijn Hanssen, Samo Penič, Aleš Iglič, Daniel A. Fletcher, Valentin Jaumouillé, Daan Vorselen, Verena

Published 2026-07-14

📖 5 min read🧠 Deep dive

CC BY 4.0

Original authors: Shubhadeep Sadhukhan, Caitlin E. Cornell, Mansehaj Kaur Sandhu, Marta Batet Palau, Youri Peeters, Stijn Hanssen, Samo Penič, Aleš Iglič, Daniel A. Fletcher, Valentin Jaumouillé, Daan Vorselen, Verena Ruprecht, Nir S. Gov

Original paper licensed under CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

Imagine a cell as a hungry, shape-shifting Pac-Man, and its target (a dying cell, a bacterium, or a cancer cell) as a piece of food. For years, scientists thought the only thing that mattered was the "flavor"—the chemical signals telling the cell, "Hey, eat me!" But a new study suggests that the texture of the food is just as important as the flavor. In fact, how hard or soft the target is can completely change how the cell tries to eat it.

The researchers, using a mix of computer simulations and real-life experiments, discovered that the stiffness of a target acts like a traffic light for the cell's eating habits. Depending on how squishy or stiff the target is, the cell switches between three very different modes of interaction: biting, pushing, or swallowing whole.

The Three Ways to Eat

The study suggests that the cell doesn't just blindly grab onto things. It uses a special "curvature-sensing" system (think of it as a GPS that detects how curved a surface is) to guide its actin muscles. Here is how the stiffness of the target changes the game:

The "Bite" (Trogocytosis): For Very Soft Targets
If the target is extremely squishy (like a wet marshmallow), the cell tries to grab it, but the target deforms too much. Instead of wrapping around the whole thing, the cell ends up taking a small "bite" out of it. In the simulations, this looked like the cell pinching off a tiny piece of the target and leaving the rest behind. The paper suggests this happens because the soft target bends so much that the cell's "muscles" can't get a good grip to wrap all the way around.
The "Push" (The Middle Ground): For Medium-Stiff Targets
This is the most surprising discovery. If the target is in the middle—neither rock-hard nor super-soft—the cell tries to eat it, but the target pushes back. The cell's muscles push against the target, but because the target is just stiff enough to resist being wrapped, the cell ends up shoving it away. The paper explicitly rules out the idea that the cell is just "giving up"; instead, it shows that the physics of the situation forces the cell to push the target out of the way rather than engulf it. In experiments with soft hydrogel beads (at 1.3 kPa), the cells were seen actively displacing them, whereas stiffer beads (at 80 kPa) were swallowed whole.
The "Swallow" (Complete Engulfment): For Stiff Targets
If the target is stiff (like a firm grape or a rigid bacterium), the cell can easily wrap its membrane around it and swallow it whole. The simulations showed that for very stiff targets (with a bending modulus of 1250 kBT), the cell smoothly encircles the object. The paper notes that this works best because the stiff target doesn't deform enough to confuse the cell's curvature sensors.

How They Knew This

The team didn't just guess; they built a digital world to test their ideas. They created a computer model where two "vesicles" (bubble-like cells) could interact. One was the eater, and the other was the food. By changing the "bending rigidity" (a measure of stiffness) of the food bubble, they watched what happened.

In the simulations, they saw that as they made the target stiffer, the behavior shifted from biting to pushing to swallowing.
They also tested this in the real world. They used Giant Unilamellar Vesicles (GUVs)—basically giant soap bubbles filled with sugar water. By changing the sugar concentration, they could make the bubbles tight (high tension) or loose (low tension).
- High tension (stiff) GUVs were swallowed.
- Low tension (soft) GUVs were either pushed away or had pieces bitten off.
They even watched this happen inside zebrafish embryos. They injected soft synthetic beads (at 1.3 kPa) and stiff beads (at 80 kPa) into the fish. The cells in the fish pushed the soft beads around but swallowed the stiff ones. They also watched macrophages (immune cells) interact with lymphoma cells (a type of cancer cell). Some cancer cells were pushed, some were bitten, and some were swallowed, suggesting that cancer cells have a wide range of stiffness.

What This Means (and What It Doesn't)

The paper suggests that the mechanical properties of a target—how hard or soft it is—are a key factor in how our immune system clears away dead cells or invaders. It's not just about chemical signals; the physical "feel" of the target matters.

However, the authors are careful to say that this is a mechanical explanation. They explicitly state that these different behaviors (biting, pushing, swallowing) arise from the physical interaction between the cell's forces and the target's shape. They do not claim that the cell is using a different chemical "recipe" or signaling pathway for each mode; rather, the same mechanical rules just produce different outcomes based on stiffness.

The study also notes that while they focused on the "pushing" forces of actin (the cell's muscle fibers), they did not include the "squeezing" forces of myosin (another type of motor protein) in their main model, though they acknowledge myosin plays a role later in the process.

In short, the paper proposes that the immune system is like a chef who changes their cooking technique based on the texture of the ingredient. If the ingredient is too soft, they might just take a nibble. If it's too squishy in the middle, they might just shove it aside. But if it's just right, they can wrap it up and eat it whole. This helps explain why sometimes cells clear away dead tissue efficiently, and other times they seem to struggle or push things away instead.

Technical Summary: From Biting to Engulfment: Target Mechanics Determines Modes of Phagocytosis through Curvature–Actin Coupling

Problem Statement
Phagocytosis is a fundamental innate immune process responsible for clearing pathogens, apoptotic cells, and cancer cells. While molecular recognition signals are well-characterized, the role of target mechanics in regulating the mode of phagocyte–target interaction remains poorly understood. Existing theoretical models often assume rigid targets, which is appropriate for bacteria or fungi but fails to account for the substantial shape changes observed when phagocytes engage soft targets like dying cells or antibody-opsonized cancer cells. The central question addressed is how target stiffness governs the transition between different modes of interaction, such as complete engulfment, displacement (pushing), or partial extraction (biting/trogocytosis).

Methodology
The authors employ a combined approach of theoretical modeling and experimental validation:

Theoretical Model:
- Framework: A Monte-Carlo (MC) simulation of two interacting, deformable, closed 3D triangulated vesicles (representing the phagocyte and the target).
- Mechanism: The model incorporates curvature-sensitive membrane complexes (CMC) that recruit and nucleate actin polymerization. These CMCs generate active protrusive forces directed along the local outward normal.
- Key Variables: The model varies the bending modulus ( $\kappa$ ) of the target vesicle to simulate different stiffness levels and includes adhesion energy ( $E_{ad}$ ) and osmotic pressure.
- Dynamics: The simulation tracks the evolution of membrane shape, the alignment of active forces (tangential vs. normal components), and the resulting adhesion area. It explicitly models the feedback loop between target deformation and the orientation of actin-driven forces.
Experimental Validation:
- In Vivo: Zebrafish embryos were used to observe epithelial clearance of apoptotic targets. Synthetic "lipobeads" with tunable stiffness (1.3 kPa vs. 80 kPa) and Bax-induced apoptotic cells were introduced to test clearance behaviors.
- In Vitro (GUVs): Macrophages were co-cultured with Giant Unilamellar Vesicles (GUVs) of varying membrane tension (controlled by osmotic pressure) to observe engulfment dynamics.
- In Vitro (Cells): Time-lapse microscopy of macrophages interacting with antibody-opsonized lymphoma cells (Raji cells) to observe interactions with heterogeneous cancer cell populations.

Key Contributions and Results

Identification of Three Mechanical Regimes:
The theoretical model predicts three distinct dynamical phases based on target stiffness (or membrane tension):
- Engulfment (Stiff Targets): For high bending rigidity (or high internal pressure), the target resists deformation. The CMCs align tangentially to the target surface, generating forces that efficiently wrap the membrane around the target, leading to complete phagocytosis.
- Pushing (Intermediate Stiffness): For targets with intermediate stiffness, the target deforms under the active forces. This deformation misaligns the CMCs, causing a significant normal (pushing) force component. The target is displaced rather than engulfed, and the interaction eventually stalls or retracts.
- Biting/Trogocytosis (Soft Targets): For very soft targets, the target undergoes large deformations. The CMCs cannot align tangentially; instead, they impinge on the target, generating a mix of normal and tangential forces that result in the extraction of a small portion of the target membrane (biting) without full engulfment.
Mechanism of Curvature–Actin Coupling:
The study elucidates that these transitions arise purely from physical interactions and the coupling between membrane curvature and actin recruitment. As the target deforms, the local curvature changes, altering the orientation of the CMCs and the direction of the active forces. This feedback loop determines whether the forces promote spreading (engulfment) or displacement (pushing/biting).
Experimental Confirmation:
- Zebrafish: Soft lipobeads (1.3 kPa) were frequently pushed away by epithelial cells, whereas stiff lipobeads (80 kPa) were exclusively engulfed. Apoptotic cells (which soften) exhibited high mobility consistent with the "pushing" regime.
- GUVs: High-tension GUVs were fully engulfed, while low-tension GUVs exhibited a mix of pushing and biting (trogocytosis).
- Lymphoma Cells: Macrophages displayed all three behaviors (engulfment, pushing, and biting) when interacting with a population of lymphoma cells, suggesting these cells possess a heterogeneous range of stiffness.
Role of Spatial Constraints:
The study demonstrates that local tissue geometry can modulate outcomes. When soft targets were mechanically constrained (e.g., held by neighboring cells), they were successfully engulfed. This suggests that confinement allows the protrusive forces to align tangentially, overcoming the "pushing" instability predicted for unconstrained soft targets.

Significance
The paper claims to establish target mechanics as a key regulator of phagocyte behavior, independent of stiffness-dependent signaling pathways. The findings provide a general physical mechanism explaining how the mechanical state of a target (stiffness, tension, deformability) dictates the mode of clearance. This offers a mechanistic explanation for:

The variability in phagocytosis efficiency for soft targets (e.g., soft beads vs. rigid bacteria).
The observation of "pushing" behaviors in embryonic development and tissue homeostasis.
The occurrence of trogocytosis (biting) in immune interactions.

By identifying that the "pushing" regime emerges at intermediate stiffness, the work bridges the gap between complete engulfment and partial extraction, suggesting that the mechanical properties of targets (such as apoptotic cells or cancer cells) are critical determinants in immune surveillance and tissue homeostasis. The authors note that their model focuses on the recruitment of actin and protrusive forces, excluding contractile forces (myosin-II), which are typically active in later stages.

The Three Ways to Eat

How They Knew This

What This Means (and What It Doesn't)

Technical Summary: From Biting to Engulfment: Target Mechanics Determines Modes of Phagocytosis through Curvature–Actin Coupling

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