Fibroblast activation protein is a molecule that appears at very high levels in the tumor microenvironment, on bone marrow mesenchymal stem cells, and on stromal fibroblasts that surround and support growing tumors. Because healthy adult tissues express very little of this protein, it has become one of the most attractive targets in oncology. Conventional FAPI-based radiotracers have already shown impressive results in positron emission tomography imaging of many cancer types. However, the review argues that simply targeting FAP with small molecules leaves much of the potential untapped.

The crucial novelty, according to the researchers, lies in conjugating FAPIs to nanoparticles rather than using them alone. This combination brings together the precise targeting ability of FAP inhibitors with the considerable advantages of nanoscale carriers: enhanced loading of drugs or radionuclides, prolonged retention inside tumors, and the possibility of building multifunctional theranostic platforms, systems that can simultaneously diagnose and treat disease, all within a single structure. In other words, one engineered particle could theoretically find a tumor, light it up on a scanner, and deliver a therapeutic payload at the same time.

To assess where the field actually stands, the team conducted a comprehensive systematic search across PubMed, Scopus, Embase, Web of Science, and Google Scholar, covering publications up to June 29, 2025. They used medical subject headings and keywords combining fibroblast activation protein inhibitor or FAPI with nanoparticles. After removing duplicates, book chapters, non-English articles, reviews, and conference abstracts, and screening titles and abstracts for relevance, the initial pool of 106 studies was narrowed down to just nine original research papers covering both cancerous and non-cancerous diseases.

That small number is itself telling. Despite enormous excitement about FAP-targeted nanomedicine, only a handful of studies have actually built and tested FAPI-conjugated nanoparticles in laboratory models. The nine included studies explored a remarkably diverse set of nanomaterials, including manganese dioxide-coated calcium phosphate microspheres, mesoporous polydopamine nanoparticles, lutetium-177 oxide particles, astatine-211-labeled polydopamine, polymersomes, organic room-temperature phosphorescent probes, and lutetium-177 DOTA-polyethylene glycol-labeled polydopamine structures.

The applications were equally varied. Researchers have investigated these FAPI-nanoparticle systems for osteoporotic bone defects, pulmonary fibrosis, colorectal cancer, liver metastases, glioma and glioblastoma, breast cancer, and liver cancer. This breadth reflects the fact that fibroblast activation protein is not exclusive to malignancy; it also plays a role in fibrotic and remodeling diseases, which opens therapeutic avenues well beyond oncology. Characterization data from the studies showed that the geometric sizes of the nanoparticles, measured by transmission electron microscopy, and their hydrodynamic sizes, measured by dynamic light scattering, ranged from approximately 20 to 200 nanometers and 60 to 320 nanometers respectively, dimensions well suited to accumulating in tumor tissue through the leaky vasculature characteristic of cancer.

The preclinical results reported across the nine studies were consistently encouraging. The conjugated systems demonstrated enhanced targeting of diseased tissue, prolonged retention within tumors, increased generation of reactive oxygen species, which can directly kill cancer cells, and reduced fibrosis in relevant disease models. These findings support the core hypothesis of the field: that anchoring a FAP-targeting ligand to a nanoparticle amplifies both diagnostic sensitivity and therapeutic effect compared with either component alone.

Yet the authors are careful to temper enthusiasm with scientific rigor. Because only nine studies met the inclusion criteria, and because those studies used highly heterogeneous nanoparticle types, disease models, and outcome measures, the evidence base remains thin. More importantly, the review found insufficient data on long-term safety, toxicity, biodistribution, and clearance, the very parameters that regulatory agencies scrutinize most closely before allowing human trials. A nanoparticle that performs brilliantly in a mouse model may behave very differently in patients, accumulating in the liver or spleen, triggering immune reactions, or clearing too slowly for repeated dosing.

The authors therefore conclude that the current findings should be interpreted cautiously, and they call for further preclinical work and well-designed clinical studies before FAPI-conjugated nanoparticles can be confidently translated into routine practice. That translation path is well trodden in one sense: FAPI-based imaging agents have already entered clinical use for cancer detection, providing a regulatory and scientific foundation on which nanoparticle versions could build. What remains is to prove that the added complexity of nanocarriers, their synthesis, characterization, stability, and safety, delivers benefits that justify the effort.

If those hurdles are cleared, the payoff could be substantial. A single FAPI-conjugated nanoparticle capable of carrying a therapeutic radionuclide like lutetium-177 or astatine-211 while also serving as an imaging agent would embody the theranostic ideal that has driven nuclear medicine for decades. For patients with glioblastoma, liver cancer, or metastatic disease, where precision in both diagnosis and treatment can determine survival, such platforms could offer a genuinely new option. The systematic review provides a clear map of what has been achieved so far and, just as importantly, an honest accounting of how much work lies ahead.

Subject of Research: FAPI-conjugated nanoparticles for targeted cancer imaging and therapy

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

Article References: Abbasi, S., Irajirad, R., Khademi, S., Fathabadi, A., Dehghani, M., Montazerabadi, A., Sadeghi, M., & Tavakoli, M. (2026). Translational insights from FAPI-conjugated nanoparticles: a systematic review of current applications and future directions. BMC Cancer. https://doi.org/10.1186/s12885-026-17075-y

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17075-y

Keywords: FAPI, fibroblast activation protein, nanoparticles, tumor microenvironment, targeted drug delivery, theranostics, cancer, radionuclide therapy, systematic review, polydopamine, preclinical studies, BMC Cancer