Biomaterial and bioorthogonal surface engineering of a modular dextran–lipid nanoplatform for tumorresponsive cytokine delivery
5 affiliations
- 1Department of Health Technology
- 2Technical University of Denmark
- 3Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, Copenhagen, Denmark, DK-2100
- 4National Centre for Nanofabrication and Characterization
- 5Department of Pharmacy, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark, DK-2100
Abstract
Cytokine-based immunotherapy holds considerable promise for cancer treatment, but its clinical translation is constrained by systemic toxicity, rapid clearance, and limited tumor selectivity. Here, we engineered a modular dextran–lipid nanoplatform that integrates biomaterial design with bioorthogonal surface functionalization for tumor-responsive cytokine delivery (Fig. 1). Azide-functionalized dextran was chemically modified to tune its physicochemical properties and subsequently assembled with an ionizable lipidoid to form hybrid nanoparticles with reactive surface handles. Pro-inflammatory cytokines were covalently displayed on the nanoparticle surface through strain-promoted azide–alkyne cycloaddition, followed by installation of an enzyme-cleavable linker and a PEG-based steric shield. In the tumor microenvironment, tumor-associated proteases cleave the linker, removing the shielding layer and restoring accessibility of the surface-bound cytokine without requiring its complete release from the carrier, as schematically illustrated in Fig. 1. Using IL-18 as a model cytokine, the platform enabled efficient surface conjugation while preserving cytokine bioactivity, and enzyme-triggered de-shielding resulted in time-dependent recovery of biological activity in vitro. The nanoparticles also exhibited good colloidal stability and biocompatibility under the investigated conditions. Overall, this work establishes a modular biomaterial platform in which programmable surface chemistry enables controlled cytokine presentation and tumor-responsive activation, providing a versatile strategy for localized protein-based immunotherapy.
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BibTeX
@misc{zhang2026biomaterial,
title = {{Biomaterial and bioorthogonal surface engineering of a modular dextran–lipid nanoplatform for tumorresponsive cytokine delivery}},
author = {Jing Zhang and Tao Zheng and José Moreira and Murat Nulati Yesibolati and Mingshi Yang and Holger Grohganz and Yi Sun},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008224/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008224/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Biomaterial and bioorthogonal surface engineering of a modular dextran–lipid nanoplatform for tumorresponsive cytokine delivery
AU - Jing Zhang
AU - Tao Zheng
AU - José Moreira
AU - Murat Nulati Yesibolati
AU - Mingshi Yang
AU - Holger Grohganz
AU - Yi Sun
PY - 2026
DA - 2026/09/02
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008224/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008224/v1
AB - Cytokine-based immunotherapy holds considerable promise for cancer treatment, but its clinical translation is constrained by systemic toxicity, rapid clearance, and limited tumor selectivity. Here, we engineered a modular dextran–lipid nanoplatform that integrates biomaterial design with bioorthogonal surface functionalization for tumor-responsive cytokine delivery (Fig. 1). Azide-functionalized dextran was chemically modified to tune its physicochemical properties and subsequently assembled with an ionizable lipidoid to form hybrid nanoparticles with reactive surface handles. Pro-inflammatory cytokines were covalently displayed on the nanoparticle surface through strain-promoted azide–alkyne cycloaddition, followed by installation of an enzyme-cleavable linker and a PEG-based steric shield. In the tumor microenvironment, tumor-associated proteases cleave the linker, removing the shielding layer and restoring accessibility of the surface-bound cytokine without requiring its complete release from the carrier, as schematically illustrated in Fig. 1. Using IL-18 as a model cytokine, the platform enabled efficient surface conjugation while preserving cytokine bioactivity, and enzyme-triggered de-shielding resulted in time-dependent recovery of biological activity in vitro. The nanoparticles also exhibited good colloidal stability and biocompatibility under the investigated conditions. Overall, this work establishes a modular biomaterial platform in which programmable surface chemistry enables controlled cytokine presentation and tumor-responsive activation, providing a versatile strategy for localized protein-based immunotherapy.
ER -