Fine-Tuning Photochemical Immunogenic Cell Death by a Panel of Verteporfin-Lipid Nanoparticles: A Data-Driven
Nimit Shah1, Maxwell Bortei Quaye1, Siddharth Reddy Soma1
1Department of Bioengineering The University of Texas at Dallas Richardson TX 75080 USA.
Abstract:
Immunogenic cell death (ICD) is an immunostimulatory process that can be induced by light-activated photosensitizers, but its mechanisms remain unclear, especially with lipid nanoparticle (LNP) formulations. In this study, a multivariate, data-driven analysis was conducted using a panel of five verteporfin(V)-LNPs to identify the attributes that lead to the greatest photochemically-induced exposure of ICD markers in pancreatic cancer cells. These attributes include varying production of Type I (radicals) or Type II (singlet oxygen) reactive oxygen species (ROS) upon 690 nm activation, localization in different organelles, variable cellular uptake efficiencies, and different phototoxicity levels. Using principal component analysis, we identified that, unexpectedly, Type I ROS is most strongly associated with ICD marker exposure, which leads to dendritic cell activation ex vivo, while Type II ROS shows the weakest association. Furthermore, V-LNP localization in the endoplasmic reticulum and mitochondria is most strongly associated with exposure of ICD markers, while lysosomal localization shows the weakest association. ICD marker exposure is proportional to the degree of phototoxicity and cellular uptake efficiency for all V-LNPs. These findings provide critical insights into the multiparametric mechanism underlying photochemical ICD induced by V-LNPs and can inform the rational design of photochemical LNP constructs for augmenting anticancer immune responses.
Insights
Type I reactive oxygen species (ROS) and endoplasmic reticulum/mitochondria localization unexpectedly enhance immunogenic cell death (ICD) marker exposure from verteporfin-lipid nanoparticles (V-LNPs). This finding guides the design of novel photochemically-activated cancer immunotherapies.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
- Photochemistry
Background:
- Immunogenic cell death (ICD) is a crucial immunostimulatory process.
- Light-activated photosensitizers can induce ICD, but mechanisms with lipid nanoparticle (LNP) formulations are not fully understood.
- Understanding these mechanisms is vital for developing effective cancer immunotherapies.
Purpose of the Study:
- To identify key attributes of verteporfin-LNPs (V-LNPs) that maximize photochemically-induced ICD marker exposure in pancreatic cancer cells.
- To elucidate the roles of different reactive oxygen species (ROS) types, organelle localization, cellular uptake, and phototoxicity in V-LNP-mediated ICD.
- To provide insights for rational design of V-LNPs for enhanced anticancer immune responses.
Main Methods:
- Multivariate, data-driven analysis of five V-LNP formulations.
- Assessment of Type I (radical) and Type II (singlet oxygen) ROS production upon 690 nm activation.
- Evaluation of V-LNP organelle localization (ER, mitochondria, lysosomes).
- Measurement of cellular uptake efficiency and phototoxicity.
- Principal component analysis (PCA) to correlate attributes with ICD marker exposure.
Main Results:
- Type I ROS production was unexpectedly most strongly associated with ICD marker exposure, while Type II ROS showed the weakest association.
- V-LNP localization in the endoplasmic reticulum and mitochondria correlated most strongly with ICD marker exposure.
- Lysosomal localization showed the weakest association with ICD marker exposure.
- ICD marker exposure was directly proportional to phototoxicity and cellular uptake efficiency.
Conclusions:
- Type I ROS and specific organelle targeting (ER, mitochondria) are critical for V-LNP-mediated photochemical ICD.
- Cellular uptake and phototoxicity are key determinants of ICD marker exposure.
- Findings inform the rational design of V-LNPs to optimize anticancer immune responses via photochemical ICD induction.
