Work

Engineering and evaluation of precision-glycosylated clickable albumin nanoplatform for targeting the tumor microenvironment

Year: 2025

Type: article

Abstract: Rationale: Glycosylation of drug delivery vehicles enables selective tumor microenvironment (TME) targeting but is limited by the lack of precise glycan control and unbiased evaluation of in situ targeting.We developed a clickable albumin nanoplatform engineered by distinct glycosylation for selective in vivo cell targeting (CAN-DGIT) with a defined number of sugar moieties and integrated spatial transcriptomics (ST) to map nanoparticle-TME interactions.Methods: Albumin was functionalized with azadibenzocyclooctyne (ADIBO) at a controlled degree of functionalization (DOF), confirmed by MALDI-TOF and UV-vis spectroscopy, followed by conjugation of azide-functionalized mannose, galactose, or glucose via click chemistry.Nanoparticles were labeled with 64 Cu or fluorescent dyes for PET imaging and ex vivo analysis in healthy and 4T1 tumor-bearing mice.ST based algorithms, spatial gene-image integration (SPADE), cell-type deconvolution (CellDART), and image-based molecular signature analysis (IAMSAM), were used to define TME clusters, associated cell populations, and glycan receptor gene signatures.Clodronate-loaded glycosylated albumins were tested for tumor-associated macrophage (TAM) depletion.Results: Glycosylation type of CAN-DGIT dictated pharmacokinetics and targeting.Mannosylated albumin (Man-Alb) showed rapid hepatic retention via mannose receptors on Kupffer cells and TAMs; galactosylated albumin (Gal-Alb) exhibited rapid hepatobiliary clearance with the highest tumor-to-liver ratio; glucosylated albumin at the C6 position (Glc(6)-Alb) progressively accumulated in tumors, correlating with glucose transporter 1 (GLUT1)-expressing cancer cells.ST confirmed Man-Alb enrichment in extracellular matrix (ECM)/TAM-rich clusters (mannose receptor C-type 1, Mrc1-high) and Gal-/Glc-Alb uptake in glycolytic/hypoxic tumor clusters (Slc2a1-high).Man-Alb-clodronate achieved potent CD206+ TAM depletion without altering drug release kinetics.Conclusions: Precisely tuned glycosylation enables programmable biodistribution and cell-type targeting of albumin nanoparticles in the TME.Integrating PET with ST provides a robust framework for mechanistic mapping of nanomedicine uptake.The CAN-DGIT platform offers a versatile strategy for developing targeted theranostic agents with immunomodulatory potential.

Source: Theranostics

DOI: 10.7150/thno.123973