Key Takeaways & Executive Findings
- •• • CAMeO-Q NPs achieve synergistic low-temperature PTT by combining mitochondria-targeting photothermal agent and Hsp90 inhibitor, reversing thermal tolerance via ATP blockade and Hsp90 downregulation, with 660 nm laser irradiation inducing selective mitochondrial damage. • • The nanoplatform enables trimodal imaging (FLI, PAI, PTI) for precise tumor localization and real-time therapy monitoring, addressing penetration depth limitations of single-modality imaging. • • Homologous targeting enhances tumor accumulation and cellular uptake, improving therapeutic efficacy while minimizing off-target effects, as evidenced by in vivo melanoma models. • • The energy disruptor strategy effectively inhibits heat shock protein expression, overcoming the major bottleneck of low-temperature PTT resistance, thereby increasing cancer cell death at lower temperatures and reducing collateral damage to normal tissues.
Abstract
The evolution of precision medicine has propelled multimodal imaging-guided phototheranostics to the forefront for precise tumor diagnosis and therapy. Low-temperature photothermal therapy (PTT) offers a promising approach for the treatment of melanoma due to its non-invasiveness and minimal damage to normal tissues. However, its efficacy is limited by cancer cell thermal tolerance. To address this, a new type of multifunctional energy disruptor (CAMeO-Q NPs) is developed featuring homologous targeting and mitochondria targeting, and synergistically enhancing low-temperature PTT in melanoma by reversing heat shock protein 90 (Hsp90)-mediated thermal tolerance and blocking mitochondrial adenosine triphosphate (ATP) biosynthesis. The multifunctional energy disruptor enables precise trimodal imaging (fluorescence imaging/FLI, photoacoustic imaging/PAI, and photothermal imaging/PTI) guidance for low-temperature PTT. Comprising a mitochondria-targeting photothermal agent and an Hsp90 inhibitor, CAMeO-Q NPs induce selective mitochondrial damage under 660 nm laser irradiation and downregulate cellular HSP expression by ATP inhibition and Hsp90 inhibitor. This multifunctional energy disruptor provides a novel strategy for enhancing multimodal imaging-guided low-temperature photothermal therapy through combined homologous targeting, mitochondria-targeting, and Hsp90 inhibition.
1. Introduction
Melanoma, a highly aggressive skin cancer with rising incidence, presents a 5-year survival rate that remains unsatisfactory despite surgical excision, lymph node dissection, and chemotherapy. The urgent need for novel diagnostic and therapeutic strategies has driven the development of phototheranostics, which integrates optical imaging and phototherapy for synchronous real-time diagnosis and precisely controlled in situ treatment. However, conventional photothermal therapy (PTT) often requires high temperatures (>50°C) to ablate tumors, inevitably causing collateral damage to surrounding healthy tissues. Low-temperature PTT (<45°C) offers a non-invasive alternative with minimal damage, but its efficacy is severely hampered by cancer cell thermal tolerance mediated by heat shock proteins (HSPs), particularly Hsp90.
To overcome this bottleneck, the present work introduces a multifunctional energy disruptor (CAMeO-Q NPs) that combines homologous targeting and mitochondria targeting to synergistically enhance low-temperature PTT. By co-delivering a mitochondria-targeting photothermal agent and an Hsp90 inhibitor, the system simultaneously blocks mitochondrial ATP biosynthesis and inhibits Hsp90, thereby reversing thermal tolerance and sensitizing cancer cells to mild hyperthermia. Furthermore, the integration of trimodal imaging (FLI, PAI, PTI) provides precise guidance for therapy, addressing the limitations of single-modality imaging in penetration depth and resolution. This strategy represents a significant advancement in precision cancer therapy, offering a clinically translatable approach for melanoma treatment.
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LI Shuo, LIU Yu-Qi, ZHANG Guoyang, LI Wentao, SI Yutong, LIU Meng, ZHANG Guo-Ling, WANG Zhuo, TANG Ben Zhong, FENG Hai-Tao (2026). Multifunctional mitochondria-targeting energy disruptor for enhancing imaging-guided low-temperature photothermal therapy of melanoma. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-4081-y
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Frequently Asked Questions
What is the mechanism by which CAMeO-Q NPs overcome thermal tolerance in low-temperature PTT?
CAMeO-Q NPs incorporate an Hsp90 inhibitor and a mitochondria-targeting photothermal agent. Under 660 nm laser irradiation, the photothermal agent induces localized hyperthermia and mitochondrial damage, while the Hsp90 inhibitor downregulates Hsp90 expression. Concurrently, the disruption of mitochondrial ATP biosynthesis reduces energy supply for HSP expression, collectively reversing thermal tolerance and sensitizing cancer cells to mild hyperthermia.
How does the trimodal imaging capability of CAMeO-Q NPs improve therapeutic outcomes?
The nanoplatform integrates fluorescence imaging (FLI), photoacoustic imaging (PAI), and photothermal imaging (PTI). FLI provides high sensitivity, PAI offers deeper tissue penetration and spatial resolution, and PTI enables real-time temperature monitoring during therapy. This synergistic imaging guidance allows precise tumor localization, treatment planning, and thermal dose control, thereby enhancing therapeutic efficacy while minimizing off-target damage.
What are the potential scalability and translational challenges for CAMeO-Q NPs?
Scalability challenges include reproducible synthesis of the multifunctional nanoparticles with consistent size, surface modification, and drug loading. Translational hurdles involve biocompatibility, long-term stability, and regulatory approval. The paper does not provide specific data on scale-up yields or long-term toxicity, but the use of FDA-approved materials and clear mechanistic rationale may facilitate clinical translation.
How does the homologous targeting strategy enhance tumor accumulation and specificity?
Homologous targeting employs cancer cell membrane coating on nanoparticles, which recognizes homologous tumor cells via membrane adhesion molecules. This biomimetic approach reduces immune clearance and enhances tumor homing, leading to higher accumulation at the tumor site and improved cellular uptake, as demonstrated by in vivo imaging and therapeutic studies.
What are the limitations of low-temperature PTT and how does this study address them?
Low-temperature PTT (<45°C) is limited by heat resistance conferred by HSPs. This study addresses it by combining Hsp90 inhibition and ATP depletion, which downregulates HSP expression and sensitizes cancer cells to mild hyperthermia. The approach enhances cancer cell death at lower temperatures, reducing collateral damage to normal tissues, as evidenced by improved therapeutic outcomes in melanoma models.
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