Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer
Clemens HinterleitneriD, Valentin J.A. BarthetiD, Hailey V. GoldbergiD, Kristen C. VogtiD, Ana Marie PereaiD, Logan R. HillgeriD, Stephen B. RuiziD, Domhnall McHughiD, Yu-Jui HoiD, Almudena Chaves PereziD, Maria SkamagkiiD, Sara Flowers, Hannah C. StyersiD, Natasha RekhtmaniD, Xueqian ZhuangiD, Gabriel Dessotti BarrettoiD, Xiang LiiD, Jadae T. WatsoniD, Wei LuaniD, Janelle M. SimoniD, Tuomas TammelaiD, Rui GardneriD, Charles M. RudiniD, Paul Bernard RomesseriD, Matthew Joseph BottiD, , Scott W. LoweiD
Abstract
Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune-checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.
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Claude Opus 5.5 · xhigh effort · 7 Nov 2026 · from the full text of version 2 (25 Aug 2026) · CC BY 4.0
P-selectin-targeted fucoidan nanoparticles carrying Navitoclax or dBET6 deplete a senescent-like, lipid-associated macrophage subset, reverse mouse liver and lung fibrosis with less toxicity, and restore checkpoint therapy response in fibrotic tumors.
Existing senotherapeutics lack cellular precision and cause on-target toxicity in normal cells, and senescent-like states in tissue are heterogeneous. The paper uses P-selectin as a handle to deliver senolytic or senomorphic payloads to one pathogenic macrophage subset in fibrotic niches.
Key results
ShownP-selectin marks a subset of senescent-like cells in human and mouse fibrotic liver and lung, and it is raised in fibrotic tissue relative to non-fibrotic tissue.
58 human liver and lung fibrosis specimens plus controls by IHC and multiplex IF: P-selectin higher in fibrosis; a subset of P-selectin+ cells are p21+, Ki67-negative, LaminB1-low. Mouse CCl4 and bleomycin models agree, with P-selectin enriched near α-SMA-dense regions. · P-selectin marks senescent-like cells in…; Figure legends
ShownFucoidan nanoparticles loaded with Navitoclax (FiNav) or dBET6 (FidBET6) reverse established fibrosis in mouse liver and lung while removing the hematologic toxicity of the free drugs.
Collagen and α-SMA+ fibroblasts fell at least as much as with free drug; dextran control particles and free fucoidan were ineffective. SMNPs eliminated neutropenia and thrombocytopenia, shortened bleeding times, and protected against weight loss and treatment-associated mortality (4-6 mice/group). · SMNPs reverse established fibrosis while…; Figure legends
ShownThe functional in vivo target is a P-selectin+/SA-β-gal+ macrophage population (MΦP+sen+). Selectivity depends on P-selectin uptake, lysosomal routing in macrophages and a senescence-matched payload.
Ex vivo, FiNav killed only MΦP+sen+ cells among sorted macrophage and endothelial subsets, and FidBET6 degraded Brd4 only in them. P-selectin blockade reduced uptake. FiNav depleted these cells within 36 hours, before fibrosis resolved. Paclitaxel particles (FiPax) killed P-selectin+ macrophages regardless of senescence and had weaker antifibrotic effect. · SMNPs target a subset of senescent-like…; Figure legends
ShownIn mouse fibrotic liver and lung tumors, FiNav remodels the stroma and, combined with first-line checkpoint-based therapy, overcomes resistance and gives durable regression.
Tumors that responded in non-fibrotic organs were refractory in fibrotic ones. FiNav alone dismantled stromal barriers but only modestly inhibited growth. FiNav plus therapy gave durable regression and better survival, with lymphoid aggregates and DC:CD4:CD8 triads. CD8+ depletion largely abrogated the benefit; FidBET6 worked in the liver model. · SMNPs can reverse immunotherapy resistance; Figure legends
SuggestedA humanized MΦP+sen+ signature with lipid-associated macrophage features is expanded in human fibrosis and tumors, and these cells are enriched in non-responders to anti-PD-1 chemo-immunotherapy.
Signature enriched in public human fibrosis scRNA-seq (liver: 44 healthy, 5 cirrhotic; lung: 51 healthy, 66 fibrotic) and found in HCC (n=79) and NSCLC (n=12) data. In 19 NSCLC patients on neoadjuvant therapy, these cells were significantly enriched in non-responders; FiNav killed them ex vivo in 3 patient specimens. · SMNP-targeted macrophage populations are related…; SMNPs target a conserved senescent-like…; Figure legends
Methods, data and reproducibility
Fucoidan or dextran nanoparticles were formulated with Navitoclax, dBET6 or paclitaxel and tested in CCl4 liver and bleomycin lung fibrosis mice and in fibrotic tumor models. Targets were mapped by FACS on P-selectin and SA-β-gal, scRNA-seq, multiplex IF and ex vivo killing, then compared with human datasets and patient tissue.
- Human liver and lung fibrosis tissue microarrays with controls (IHC and multiplex IF) · human · n = 58 fibrotic specimens plus healthy controls
- Mouse CCl4 liver and bleomycin lung fibrosis models and fibrotic tumor models (MP liver, KP lung cancer cells) · mouse · n = typically 3-10 mice/group
- Mouse scRNA-seq of sorted P-selectin/SPiDER populations from fibrotic liver and lung · mouse · GSE319261
- Public human liver and lung fibrosis myeloid scRNA-seq atlas · human · n = liver 44 healthy and 5 cirrhotic; lung 51 healthy and 66 fibrotic · SCP2156
- Public scRNA-seq of human HCC and lung adenocarcinoma · human · n = HCC n=79; NSCLC n=12 (9 LUAD samples in the GEO set) · HRA001748; GSE253013
- Multiplex IF of human HCC and NSCLC tumor microarrays · human · n = 16 HCC and 48 NSCLC patients
- Prospective NSCLC cohort on neoadjuvant anti-PD-1 plus carboplatin and pemetrexed · human · n = 19 patients
- Fresh resected NSCLC specimens for ex vivo nanoparticle killing · human · n = 3 patients
- Methods & tools
- CellRanger v8.0.1, CellBender v0.3.0, scanpy v1.10.4, scVI/scANVI, CellTypist, PhenoGraph, MAST v3.22, Seurat, Harmony, HALO, CellDive, GraphPad Prism v10
- Reagents & environment
- Software versions are stated for CellRanger, CellBender, scanpy, rapids_singlecell, MAST, PhenoGraph and Prism; no container or requirements file is mentioned.
- Reproducibility gaps
- No analysis code link is given. Multiplex IF images are not deposited and are available from the corresponding author on reasonable request. Signatures are said to be in Tables S4-6.
Limitations (5)
- Senescence and lipid-associated programs are not exclusive to MΦP+sen+ cells; other macrophage subtypes also express them, so the population is defined by P-selectin plus SA-β-gal rather than by a unique program. · stated by the authors
- FACS on the nanoparticle dye signal was not consistently achievable, so target cells were inferred by sorting on endogenous P-selectin and a SA-β-gal probe. · stated by the authors
- FiNav monotherapy remodeled the fibrotic tumor niche but did not achieve durable tumor control without checkpoint-based therapy. · stated by the authors
- Efficacy and toxicity data come from small mouse groups (often 3-6 per group) of male C57BL/6N mice, and the tumor models had Selp silenced, so effects of tumor P-selectin were not tested. · noted in this summary
- Human support is correlative and small: 19 patients for response association and 3 specimens for ex vivo killing; no human treatment data with SMNPs. · noted in this summary
Who should read:Read this if you work on senescence, fibrosis or tumor immune exclusion and want a macrophage-targeted nanoparticle strategy with scRNA-seq and spatial evidence.
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