Nanogel-controlled delivery of caerin peptides enables sustained intratumoural retention and immunometabolic reprogramming

Jinyi Wu; Hongyin Wu; Junjie Li; Xiaosong Liu; Yuandong Luo; Quanlan Fu; Sixin Guo; Zhijun Lin; Yongxin Liang; Bin Xu; Furong Zhong; Cheng Wen; Guoying Ni; Zhongyan Wang; Tianfang Wang

doi:10.1016/j.jconrel.2026.115096

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Nanogel-controlled delivery of caerin peptides enables sustained intratumoural retention and immunometabolic reprogramming

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Nanogel-controlled delivery of caerin peptides enables sustained intratumoural retention and immunometabolic reprogramming

Jinyi Wu, Hongyin Wu, Junjie Li, Xiaosong Liu, Yuandong Luo, Quanlan Fu, Sixin Guo, Zhijun Lin, Yongxin Liang, Bin Xu, …

Journal of Controlled Release, Vol.396, pp.1-19

2026

DOI: https://doi.org/10.1016/j.jconrel.2026.115096

PMID: 42276236

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Abstract

Self-assembling peptide

Antigen presentation

Host-defence peptides

Nanogel

Caerin 1.1/1.9

Cancer immunotherapy

Immunometabolic reprogramming

Controlled release

Tumour microenvironment

Intratumoural delivery

Host-defence peptides possess both direct cytotoxic and immunomodulatory activities but their therapeutic application is limited by rapid degradation and insufficient intratumoural retention. Here, we report a self-assembling nanogel delivery system that enables sustained intratumoural release of the amphibian peptides caerin 1.1 and 1.9 (F1/F3) and enhances their antitumour efficacy. F1/F3 suppressed tumour growth in immune-competent and PBMC-humanised mouse models but showed minimal activity in immunodeficient mice, confirming a predominantly immune-dependent mechanism. To overcome delivery limitations, F1/F3 was encapsulated within the self-assembled nanofibrous network of the short D-configuration peptide Nap-GDFDFDY (NAP-GFFY) to form an injectable nanogel (F1/F3–NAP-GFFY). Physicochemical characterisation demonstrated that the nanogel formed a stable supramolecular nanofibrous structure with sustained-release properties and structural stability under acidic, enzymatic, and thermal stress conditions. Nanogel-mediated delivery significantly prolonged intratumoural peptide retention following local administration and resulted in enhanced tumour suppression and prolonged survival compared with free peptide treatment. Mechanistically, nanogel-mediated delivery induced coordinated reprogramming of the tumour microenvironment. Integrated transcriptomic, proteomic and metabolomic analyses revealed activation of antigen processing and presentation pathways, interferon-responsive signalling, cytotoxic immune programs and inflammasome-associated responses. Concurrent metabolic alterations, including lipid remodelling, mitochondrial β-oxidation and redox regulation, indicated adaptive immunometabolic restructuring. These changes were accompanied by increased infiltration of CD4+ and CD8+ effector T cells, expansion of dendritic cell populations and reduction of immunosuppressive monocytic MDSCs in tumours and draining lymph nodes. This study demonstrates that nanogel-controlled delivery transforms F1/F3 into a sustained local immunotherapeutic system that integrates controlled release, prolonged tumour retention and immune activation. This work highlights the potential of self-assembling peptide nanogels as a versatile platform for enhancing peptide-based cancer immunotherapy.

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Title: Nanogel-controlled delivery of caerin peptides enables sustained intratumoural retention and immunometabolic reprogramming
Authors: Jinyi Wu - Guangdong Pharmaceutical University
Hongyin Wu - Guangdong Pharmaceutical University
Junjie Li - Zhongao Biomedical Technology (China)
Xiaosong Liu - Guangdong Pharmaceutical University
Yuandong Luo - Zhongao Biomedical Technology (China)
Quanlan Fu - Zhongao Biomedical Technology (China)
Sixin Guo - Zhongao Biomedical Technology (China)
Zhijun Lin - Guangdong Pharmaceutical University
Yongxin Liang - Zhongao Biomedical Technology (China)
Bin Xu - Guangdong Pharmaceutical University
Furong Zhong - Guangdong Pharmaceutical University
Cheng Wen - Chinese Academy of Medical Sciences & Peking Union Medical College
Guoying Ni (Corresponding Author) - First People's Hospital of Foshan
Zhongyan Wang (Corresponding Author) - Chinese Academy of Medical Sciences & Peking Union Medical College
Tianfang Wang (Corresponding Author) - University of the Sunshine Coast
Publication details: Journal of Controlled Release, Vol.396, pp.1-19
Publisher: Elsevier BV
Date published: 2026
DOI: 10.1016/j.jconrel.2026.115096
ISSN: 1873-4995
PMID: 42276236
Data Availability: This study's raw sequencing data is under controlled access and available from the corresponding author upon reasonable request.
Grant note: This study was supported in part by the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Science and Technology Department (2016A020213001), the National Science Foundation of Guangdong province (2020A1515010855), The Deng Feng Project of First People's Hospital of Foshan (2019A008), the National Science Fund of China (32271465), the Tianjin Natural Science Foundation Project (24JCYBJC00670), the CAMS Innovation Fund for Medical Sciences (2025-I2M-XHXX-151).
Organisation Unit: School of Science and Engineering - Legacy; GeneCology Research Centre - Legacy; School of Science, Technology and Engineering
Language: English
Record Identifier: 991240388002621
Output Type: Journal article

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