Presentation Information
[4FMBS-12]Precision Sortase Engineering of FAP-Targeted Ferritin Nanocarriers Enables Dual-Targeted Drug Delivery and Immune Remodeling in Glioblastoma
○Yi-Hsiang Tseng1, Jia-Yu Lin1, Feng-Ting Huang1, Chiun-Wei Huang2 (1. Department of Biochemical Science & Technology, National Taiwan University, Taipei, 106319 Taiwan. (Taiwan), 2. Department of Medical Research, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan (Taiwan))
Keywords:
Glioblastoma,Fibroblast activation protein,Ferritin-based drug carrier,Sortase-mediated ligation,Immunogenic Cell Death
[Purpose]
Glioblastoma (GBM) is an aggressive brain tumor characterized by a dense stromal barrier, diffuse infiltration, and poor drug delivery. Fibroblast activation protein (FAP), highly expressed on cancer-associated fibroblasts (CAFs), represents a promising yet underexploited target for overcoming stromal barriers in GBM. Here, we developed a precision-engineered nanoplatform that targets FAP to enhance drug delivery and remodel the immunosuppressive tumor microenvironment.
[Method]
We engineered a modular ferritin-based drug carrier (FDC) displaying an optimized FAP-targeting ligand while retaining intrinsic transferrin receptor-1 (TfR1) binding capability, creating a dual-targeting delivery system. To avoid the heterogeneity associated with conventional chemical conjugation, we employed an evolved Sortase A–mediated ligation strategy to achieve strictly site-specific peptide conjugation at the N-terminus of the human ferritin heavy chain (HFn). This orthogonal enzymatic approach ensured precise functionalization while preserving nanocage integrity. Monomethyl auristatin E (MMAE) was subsequently encapsulated using a pH-mediated self-assembly loading strategy.
[Results]
In orthotopic GL261 glioma models, MMAE@FAPtp-HFn nanocarriers efficiently crossed the blood–brain barrier through TfR1-mediated transcytosis and selectively targeted FAP-expressing CAFs within the tumor microenvironment. This targeted delivery significantly prolonged the median survival of glioma-bearing mice (by 25%) while minimizing systemic toxicity.
[Consideration]
Single-cell spatial transcriptomics (10x Genomics Visium HD) and immunohistochemical analyses revealed profound therapeutic remodeling of the tumor microenvironment. Targeted MMAE delivery induced robust immunogenic cell death (ICD), promoting the recruitment of cytotoxic T lymphocytes into the tumor core. This process enhanced spatial interactions between immune cells and CAFs and triggered the induction of interferon-stimulated genes, including CXCL10, suggesting potential synergy between FAP-targeted therapy and immunotherapy.
[Conclusion]
By integrating highly specific FAP-targeted delivery with precision Sortase A engineering, this ferritin-based nanoplatform effectively overcomes stromal barriers in GBM. The resulting targeted cytotoxicity stimulates antitumor immune recruitment and promotes the conversion of immunologically “cold” GBM into a more responsive “hot” tumor state. These findings support a therapeutic strategy combining CAF modulation with immunotherapy to achieve durable tumor control.
Glioblastoma (GBM) is an aggressive brain tumor characterized by a dense stromal barrier, diffuse infiltration, and poor drug delivery. Fibroblast activation protein (FAP), highly expressed on cancer-associated fibroblasts (CAFs), represents a promising yet underexploited target for overcoming stromal barriers in GBM. Here, we developed a precision-engineered nanoplatform that targets FAP to enhance drug delivery and remodel the immunosuppressive tumor microenvironment.
[Method]
We engineered a modular ferritin-based drug carrier (FDC) displaying an optimized FAP-targeting ligand while retaining intrinsic transferrin receptor-1 (TfR1) binding capability, creating a dual-targeting delivery system. To avoid the heterogeneity associated with conventional chemical conjugation, we employed an evolved Sortase A–mediated ligation strategy to achieve strictly site-specific peptide conjugation at the N-terminus of the human ferritin heavy chain (HFn). This orthogonal enzymatic approach ensured precise functionalization while preserving nanocage integrity. Monomethyl auristatin E (MMAE) was subsequently encapsulated using a pH-mediated self-assembly loading strategy.
[Results]
In orthotopic GL261 glioma models, MMAE@FAPtp-HFn nanocarriers efficiently crossed the blood–brain barrier through TfR1-mediated transcytosis and selectively targeted FAP-expressing CAFs within the tumor microenvironment. This targeted delivery significantly prolonged the median survival of glioma-bearing mice (by 25%) while minimizing systemic toxicity.
[Consideration]
Single-cell spatial transcriptomics (10x Genomics Visium HD) and immunohistochemical analyses revealed profound therapeutic remodeling of the tumor microenvironment. Targeted MMAE delivery induced robust immunogenic cell death (ICD), promoting the recruitment of cytotoxic T lymphocytes into the tumor core. This process enhanced spatial interactions between immune cells and CAFs and triggered the induction of interferon-stimulated genes, including CXCL10, suggesting potential synergy between FAP-targeted therapy and immunotherapy.
[Conclusion]
By integrating highly specific FAP-targeted delivery with precision Sortase A engineering, this ferritin-based nanoplatform effectively overcomes stromal barriers in GBM. The resulting targeted cytotoxicity stimulates antitumor immune recruitment and promotes the conversion of immunologically “cold” GBM into a more responsive “hot” tumor state. These findings support a therapeutic strategy combining CAF modulation with immunotherapy to achieve durable tumor control.
Comment
To browse or post comments, you must log in.Log in