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Focused Acoustic Vortex-Activated Dual-Stimuli Nanoplatform Synergizes with Checkpoint Blockade to Enhance Macrophage
Yan Li1, Wanlin Jia1, Mingting Zhu1
1Key Laboratory of Biomedical Information Engineering of Ministry of Education and Department of Biomedical Engineering School of Life Science and Technology Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
Abstract:
Macrophage activation in tumor immunotherapy is hindered by the "do not eat me" evasion mechanism, mediated by the CD47-SIRPα axis. Current therapeutic strategies that solely block antiphagocytic signals show limited efficacy in solid tumors, indicating the urgent need to simultaneously enhance "eat me" signals. To this end, we developed a focused acoustic vortex (FAV)-triggered dual-stimuli-responsive nanoplatform to enhance macrophage phagocytosis. This nanoplatform consists of a liposome coloaded with Cas9/sgRNA complexes and the sonosensitizer chlorin e6 (Ce6), enabling a FAV-triggered activation cascade. Upon FAV exposure, this system facilitates (1) enhanced cellular uptake by increasing membrane permeability through cavitation; (2) activation of Ce6 to generate reactive oxygen species, inducing calreticulin exposure to enhance "eat-me" signals; and (3) disruption of endosomes/lysosomes to release the Cas9/sgRNA complexes for CD47-specific knockout. This strategy enhanced macrophage phagocytosis of tumor cells, promoted M2-to-M1 macrophage polarization, and activated T-cell-mediated immune responses, resulting in significant antitumor efficacy in the 4T1-tumor-bearing mouse model. Programmed death-ligand 1 (PD-L1) checkpoint blockade following nanoplatform activation amplified systemic immune responses, resulting in 90% inhibition of primary and 80% inhibition of distant 4T1 tumors, and long-term immune memory. This study presents a strategy for precision immunotherapy through spatiotemporally controlled modulation of phagocytic signaling pathways.
Insights
This study developed a novel nanoplatform to overcome tumor immune evasion by enhancing macrophage phagocytosis. The system effectively triggers "eat me" signals, leading to significant tumor reduction and long-term immune memory.
Area of Science:
- Biomedical Engineering
- Immunotherapy
- Nanotechnology
Background:
- Tumor immunotherapy faces challenges from macrophage "do not eat me" signals (CD47-SIRPα axis).
- Current therapies blocking these signals have limited efficacy in solid tumors.
- Enhancing macrophage "eat me" signals is crucial for effective cancer immunotherapy.
Purpose of the Study:
- To develop a focused acoustic vortex (FAV)-triggered nanoplatform for enhanced macrophage phagocytosis.
- To simultaneously increase "eat me" signals and reduce "do not eat me" signals.
- To investigate the antitumor efficacy and immune memory induction of this nanoplatform.
Main Methods:
- A dual-stimuli-responsive liposomal nanoplatform co-loaded with Cas9/sgRNA and chlorin e6 (Ce6).
- FAV exposure to trigger cavitation, reactive oxygen species (ROS) generation, and endosomal disruption.
- CD47 gene knockout and calreticulin exposure to promote phagocytosis.
- Combination therapy with programmed death-ligand 1 (PD-L1) checkpoint blockade.
Main Results:
- FAV triggered nanoplatform activation, enhancing cellular uptake and ROS production.
- Induced calreticulin exposure and CD47 knockout, boosting macrophage phagocytosis.
- Promoted M2-to-M1 macrophage polarization and T-cell responses.
- Achieved significant primary (90%) and distant (80%) tumor inhibition in a 4T1 mouse model.
- Established long-term immune memory.
Conclusions:
- The FAV-triggered nanoplatform effectively overcomes tumor immune evasion by modulating phagocytic signaling.
- This precision immunotherapy strategy demonstrates potent antitumor activity and induces lasting immune memory.
- The approach offers a promising method for enhancing cancer immunotherapy efficacy.
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