Translational insights from FAPI-conjugated nanoparticles: a systematic review of current applications and future directions

Fibroblast activation protein (FAP) is overexpressed in the tumor microenvironment (TME), bone marrow mesenchymal stem cells (BMSCs), and stromal fibroblasts, making it a highly effective target for therapeutic intervention. The crucial novelty of conjugating FAP inhibitors (FAPIs) to nanoparticles (NPs) compared to conventional FAPI-based systems, as a next-generation targeted system, depends on the combination of FAP–targeted specificity with enhanced drug or radionuclide loading, prolonged tumor retention, and multifunctional theranostic capability using a single structure. A comprehensive systematic search was conducted across PubMed, Scopus, Embase, Web of Science, and Google Scholar up to June 29, 2025, using MeSH terms and keywords such as “Fibroblast Activation Protein Inhibitor” OR “FAPI” AND “nanoparticles” OR “nanoparticle”. Duplicates, book chapters, non-English articles, reviews, and conference abstracts were excluded, and titles and abstracts were screened to select studies on FAPI, conjugated with NPs (FAPI-NPs). Evidence was synthesized based on study characteristics. This systematic review initially identified 106 studies from available datasets; after screening and excluding duplicates, irrelevant articles, studies with insufficient information, non-English publications, and non-original research, nine studies were included on both cancerous and non-cancerous diseases. Different NPs, including MnO₂-coated calcium phosphate microspheres (MM), mesoporous polydopamine (MPDA), lutetium-177 oxide (¹⁷⁷Lu₂O₃), astatine-211 (²¹¹At)-PDA, polymersomes, organic room-temperature phosphorescent (RTP) probes, and ¹⁷⁷Lu-DOTA–polyethylene glycol (PEG)-PDA, have been investigated for different applications, such as osteoporotic bone defects, pulmonary fibrosis, colorectal cancer, liver metastases, glioma/glioblastoma, breast cancer, and liver cancer. The geometric (TEM) and hydrodynamic sizes (DLS) of NPs and FAPI-NPs were reported to range approximately from 20 to 200 nm and 60–320 nm, respectively. FAPI-NPs present promising preclinical results, such as enhanced targeting process, prolonged tumor retention, increased reactive oxygen species (ROS) generation, and reduced fibrosis. However, the obtained findings should be cautiously interpreted due to the limited number of included studies, heterogeneity of NP types, and insufficient evidence about long-term safety, toxicity, biodistribution, and clearance. Therefore, further preclinical and well-designed clinical studies are needed for a confidently established clinical translation.