Liver and lung fibrosis remains one of the leading causes of death worldwide, and drugs capable of halting scarring are almost nonexistent. Nearby in the archive sit studies on how cells swallow particles, how a tumor builds its family tree, how sentinel cells construct a trap for cancer, as well as on magnetic sensors for living cells and on how neutrons kill cancer cells in different ways. What unites these works is an interest in the cellular mechanisms of disease and in ways to intervene precisely. This paper stands apart: its nearest neighbor in meaning is 0.501 away, and there is not a single work right next to it. It belongs to a thematic group that mentions bacteria, stem cells, cells and Braess's paradox in biology, but the group itself is loose. So the paper fills a gap: before it, no one had connected targeted drug delivery with the specific state of senescent macrophages in the fibrotic niche.
First, using multiplex immunofluorescence on 58 samples of human fibrotic liver and lung, they checked which cells carry P-selectin together with signs of senescence: the protein p21, absence of the division marker Ki67 and reduced lamin B1. Then they created nanoparticles from sulfated fucoidan, which binds tightly to P-selectin, and loaded them with two types of drugs: the senolytic navitoclax, which kills senescent cells, and the senomorphic dBET6, which suppresses their harmful secretions. For comparison, they made particles from dextran, which does not bind P-selectin. The particles were injected into mice with liver fibrosis (induced by carbon tetrachloride) or lung fibrosis (induced by bleomycin), and their accumulation was tracked using the dye indocyanine green. To understand which cells take up the particles, cells were isolated from fibrotic organs by surface P-selectin and senescence-associated beta-galactosidase activity, and then analyzed by single-cell RNA sequencing.
In human and mouse fibrotic tissue, P-selectin appeared on a subset of senescent cells, and the picture matched in liver and lung. Fucoidan nanoparticles accumulated specifically in the diseased organ: in the liver during liver fibrosis, in the lungs during lung fibrosis. At the cellular level, they entered senescent macrophages with signs of P-selectin and beta-galactosidase, but not other cells. Both types of nanoparticles reduced collagen deposition and the number of activated fibroblasts, and the effect was no worse than that of the free drug, even though the nanoparticles affected only a small fraction of cells. Most importantly, the severe side effects of the free drugs disappeared: the drop in neutrophils and platelets, weight loss, and death of the animals. Single-cell sequencing showed that the target is a distinct macrophage population combining features of senescence and lipid-associated macrophages. These cells secrete immunosuppressive molecules and live next to activated fibroblasts, crowding out T cells. After removal of such macrophages, dendritic cells, CD4+ and CD8+ T lymphocytes returned to the tissue, and the cytokine profile shifted from anti-inflammatory to immunostimulatory. In models of liver and lung cancer grown on a fibrotic substrate, the nanoparticles combined with immunotherapy caused lasting tumor shrinkage and extended the lives of the mice, whereas without the nanoparticles the tumors did not respond to treatment.
The work differs from its neighbors in the archive in that it does not merely describe cellular states or disease mechanisms, but offers a ready technology for targeted action on a specific pathogenic population. Neighboring studies examine cellular processes one by one: how a cell swallows particles, how a tumor evolves, how immune cells recognize the enemy. Here, for the first time, it is shown that a surface marker (P-selectin) can be combined with a state of senescence and, on that basis, disease-causing macrophages can be selectively destroyed without touching beneficial ones. This is the first test of the idea that senolytics can be made safe by directing them into the right niche rather than spilling them throughout the body.
The next step is to check whether the same approach works for fibrosis of other organs, such as the kidneys or heart, and how safe it is with long-term use. A separate question: can P-selectin be used as a marker to select patients who will benefit from such therapy. If it can be shown that people with a high content of P-selectin-positive senescent macrophages have a worse prognosis, this will open the path to personalized treatment. It is also worth studying whether resistance appears with repeated courses and how the nanoparticles behave in the human body rather than in a mouse.
The technology could change the treatment of chronic liver and lung diseases, where fibrosis is currently irreversible. In oncology, it could expand the circle of patients who benefit from immunotherapy by removing the fibrotic barrier.
The immediate experiments are trials in large animals to assess toxicity and dose selection. In parallel, a diagnostic test for P-selectin-positive macrophages in biopsy samples needs to be developed in order to select patients for clinical trials.
In the biology of aging, one question remains unresolved: which senescent cells are harmful and which are beneficial. This work shows that the harm is concentrated in a small population of macrophages with a specific surface marker, and provides a tool to study it. It also remains open how senescent macrophages interact with fibroblasts and T cells in the niche, and why they in particular become resistant to immune attack.
Fucoidan is a polysaccharide from brown algae that has been used in traditional medicine in East Asia for centuries. Now it serves as a guidance system for nanoparticles because it binds tightly to P-selectin on the cell surface.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.