Modular functionalization of cellular nanodiscs enables targeted delivery of chemotherapeutics into tumors

Ilkoo Noh; Zhongyuan Guo; Rui Wang; Audrey T Zhu; Nishta Krishnan; Animesh Mohapatra; Weiwei Gao; Ronnie H Fang; Liangfang Zhang

doi:10.1016/j.jconrel.2024.12.004

Modular functionalization of cellular nanodiscs enables targeted delivery of chemotherapeutics into tumors

J Control Release. 2024 Dec 8:S0168-3659(24)00847-2. doi: 10.1016/j.jconrel.2024.12.004. Online ahead of print.

Authors

Ilkoo Noh¹, Zhongyuan Guo¹, Rui Wang¹, Audrey T Zhu¹, Nishta Krishnan¹, Animesh Mohapatra¹, Weiwei Gao¹, Ronnie H Fang², Liangfang Zhang³

Affiliations

¹ Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, Shu and K.C. Chien and Peter Farrell Collaboratory, University of California San Diego, La Jolla, CA 92093, USA.
² Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, Shu and K.C. Chien and Peter Farrell Collaboratory, University of California San Diego, La Jolla, CA 92093, USA; Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: rhfang@ucsd.edu.
³ Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, Shu and K.C. Chien and Peter Farrell Collaboratory, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: zhang@ucsd.edu.

PMID: 39657891
DOI: 10.1016/j.jconrel.2024.12.004

Abstract

The effective delivery of chemotherapeutic drugs to tumor sites is critical for cancer treatment and remains a significant challenge. The advent of nanomedicine has provided additional avenues for altering the in vivo distribution of drug payloads and increasing tumor localization. More recently, cell-derived nanoparticles, with their biocompatibility and unique biointerfacing properties, have demonstrated considerable utility for drug delivery applications. Here, we demonstrate that cell membrane-derived nanodiscs can be employed for tumor-targeted delivery. To bestow active targeting capabilities to the cellular nanodiscs, we utilize a modular functionalization strategy based on the SpyCatcher system. This enables the nanodiscs to be covalently modified with any targeting ligand labeled with a short SpyTag peptide sequence. As a proof-of-concept, a model chemotherapeutic doxorubicin is loaded into nanodiscs functionalized with an affibody targeting epidermal growth factor receptor. The resulting nanoformulation demonstrates strong tumor targeting both in vitro and in vivo, and it is able to significantly inhibit tumor growth in a murine breast cancer model.

Keywords: Cellular nanoparticle; Chemotherapy; Modular nanoparticle; SpyCatcher/SpyTag; Targeted delivery.