Evaluation of Self-Illuminating Nanoconjugates Against Pancreatic Ductal Adenocarcinoma

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer-related mortality by 2030, underscoring the need for new therapeutic approaches. While photodynamic therapy (PDT) has proven to be efficient for treating superficial solid tumors, conventional laser-dependent PDT is limited by poor tissue penetration. To address this challenge, we developed a novel self-illuminating nanoconjugate platform (SI-NCs) capable of activating PDT without external light. Methods: We engineered SI-NCs composed of the bioluminescent enzyme RLuc8 conjugated to quantum dots (QDots 705) to generate internal light for activating the FDA-approved photosensitizer verteporfin. We then evaluated SI-NC photophysical properties and assessed their ability to induce localized antitumor activity in PDAC models. Results: SI-NCs were successfully synthesized and characterized, demonstrating efficient bioluminescence resonance energy transfer and activation of verteporfin. In vitro studies in immortalized pancreatic cancer cell lines and patient-derived primary cultures revealed the mechanism of action and confirmed antitumor efficacy of bioluminescent-activated PDT. Conclusion: In vivo testing in patient-derived xenograft (PDX) models validated the therapeutic potential of SI-NCs, supporting this self-illuminating platform as a promising strategy to overcome light-penetration barriers and enhance PDT for PDAC treatment. The infographic is arranged in three main panels read from top to bottom. It shows Quantum Dots 705 plus Renilla Luciferase 8, then EDC, 1 h incubation, leading to Self-illuminating Nanoconjugates. Below are two sections: Morphology with a microscopy image and a 20 nm scale bar; and Bioluminescence Resonance Energy Transfer with a plot labeled EFRET ratio equals 8A equals 5, with labels RLuc8, QDots, A and B. Middle panel title: In vitro efficacy of Self-illuminating Nanoconjugates. A schematic labeled PDAC cells shows substrate, photosensitizer and a pipette, followed by BioLight PhotoDynamic Therapy. Outputs include a bar chart titled CELL DEATH with y-axis ticks 0, 25, 50, 75, 100, 125, 150; an image labeled APOPTOSIS; and a bar chart titled ROS with y-axis ticks 0, 100, 200, 300, 400, 500. Bottom panel title: In Vivo efficacy of Self-illuminating Nanoconjugates. A schematic labeled PDAC PDX leads to BioLight PhotoDynamic Therapy, then images labeled Control and Therapy, then text Induce cell death. The right side title reads Necrotic Area in Pancreatic tumor, with two tissue images labeled Control and BioLight PhotoDynamic Therapy.An infographic on self-illuminating nanoconjugates for photodynamic therapy, in vitro and in vivo. Keywords: photodynamic therapy, RLuc8-QDots nanoconjugates, BRET, pancreatic cancer, photosensitizer, ROS-responsive therapy