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.