As the clinical management of choroidal melanoma faces critical challenges in sensitive imaging diagnostics and effective therapeutic modalities, conventional photodynamic therapy and radiotherapy suffer from limited efficacy and severe side effects. Now, researchers from The Hong Kong University of Science and Technology, South China University of Technology, and Sun Yat-Sen University, led by Professor Ben Zhong Tang, Professor Li Ren, Professor Xuan Zhao, and Professor Jin Yuan, have presented a breakthrough AIEgen-functionalized MXene nanoplatform that enables pyroptosis-mediated precise theranostics for this aggressive intraocular malignancy.

Why This Nanoplatform Matters

Traditional photothermal/photodynamic therapies typically trigger heat-shock resistance and apoptosis-mediated cell death with limited immunogenicity. The novel MX@PEG-MeoTTPy nanosheets overcome these limitations by integrating aggregation-induced emission luminogens with MXene nanosheets—enabling type-I ROS generation for hypoxia-resistant photodynamic therapy, while inducing immunogenic pyroptosis through dual-organelle targeting. This represents a paradigm shift from conventional apoptosis to inflammatory cell death for enhanced anti-tumor immunity.

Innovative Design and Mechanism

The nanoplatform employs electrostatic assembly of cationic AIE photosensitizer PEG-MeoTTPy onto Nb₂C MXene nanosheets, encapsulated within an Agar/PSBMA thermosensitive hydrogel. Upon cellular internalization, the nanosheets undergo lysosomal escape via proton sponge effect and specifically target mitochondria through electrostatic interactions. Under dual NIR/white light irradiation, the platform generates both hyperthermia and type-I ROS (superoxide radicals and hydroxyl radicals), activating caspase-1/GSDMD-mediated pyroptosis with membrane pore formation and inflammatory cytokine release.

Outstanding Performance

MX@PEG-MeoTTPy demonstrates exceptional cancer cell selectivity with ~3-fold higher fluorescence intensity in MUM-2B cells versus normal cells, enabling precise tumor discrimination. The nanosheets achieve superior ROS generation (380-fold DCF enhancement) outperforming clinical photosensitizer Ce6, and maintain photothermal stability across five heating cycles. The stimuli-responsive hydrogel enables controlled nanosheet release over 72 hours with NIR-triggered "on-off" capability, achieving single-injection multiple-treatment convenience. In vivo studies demonstrate complete tumor ablation with normal eyeball preservation, validated by bioluminescence imaging and histopathological analysis.

Applications and Future Outlook

This work establishes a multifunctional theranostic strategy combining NIR fluorescence-photothermal dual imaging, mild photothermal-photodynamic synergistic therapy, and pyroptosis-mediated immunogenic cell death. The platform addresses critical unmet needs in choroidal melanoma management—offering sensitive noninvasive detection, precise drug delivery bypassing the blood-ocular barrier, and effective tumor eradication without enucleation—opening promising avenues for clinical translation in ocular oncology.

Stay tuned for more groundbreaking research from this collaborative team at HKUST, SCUT, Sun Yat-Sen University, and Beijing Tongren Hospital!