Photoswitchable dynamics and RNAi synergist with tailored interface and controlled release reprogramming tumor immunosuppressive niche.
Biomaterials
; 312: 122712, 2025 Jan.
Article
in En
| MEDLINE
| ID: mdl-39098305
ABSTRACT
Immunosuppressive tumor microenvironment (ITM) severely limited the efficacy of immunotherapy against triple-negative breast cancer (TNBC). Herein, Apt-LPR, a light-activatable photodynamic therapy (PDT)/RNAi immune synergy-enhancer was constructed by co-loading miR-34a and photosensitizers in cationic liposomes (in phase III clinical trial). Interestingly, the introduction of tumor-specific aptamers creates a special "Liposome-Aptamer-Target" interface, where the aptamers are initially in a "lying down" state but transform to "standing up" after target binding. The interfacing mechanism was elaborately revealed by computational and practical experiments. This unique interface endowed Apt-LPR with neutralized surface potential of cationic liposomes to reduce non-specific cytotoxicity, enhanced DNase resistance to protect aptamers, and preserved target-binding ability for selective drug delivery. Upon near-infrared irradiation, the generated reactive oxygen species would oxidize unsaturated phospholipids to destabilize both liposomes and lysosomes, realizing stepwise lysosomal escape of miR-34a for tumor cell apoptosis and downregulation of PD-L1 to suppress immune escape. Together, tumor-associated antigens released from PDT-damaged mitochondria and endoplasmic reticulum could activate the suppressive immune cells to establish an "immune hot" milieu. The collaborative immune-enhancing strategy effectively aroused systemic antitumor immunity and inhibited primary and distal tumor progression as well as lung metastasis in 4T1 xenografted mouse models. The photo-controlled drug release and specific tumor-targeting capabilities of Apt-LPR were also visualized in MDA-MB-231 xenografted zebrafish models. Therefore, this photoswitchable PDT/RNAi immune stimulator offered a powerful approach to reprogramming ITM and reinforcing cancer immunotherapy efficacy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Photochemotherapy
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Photosensitizing Agents
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MicroRNAs
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Tumor Microenvironment
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Triple Negative Breast Neoplasms
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Liposomes
Limits:
Animals
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Female
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Humans
Language:
En
Journal:
Biomaterials
Year:
2025
Document type:
Article
Country of publication: