posted on 2024-01-18, 19:05authored byEliézer Jäger, Olga Ilina, Yusuf Dölen, Michael Valente, Eric A.W. van Dinther, Alessandro Jäger, Carl G. Figdor, Martijn Verdoes
The antitumor immunity
can be enhanced through the synchronized
codelivery of antigens and immunostimulatory adjuvants to antigen-presenting
cells, particularly dendritic cells (DCs), using nanovaccines (NVs).
To study the influence of intracellular vaccine cargo release kinetics
on the T cell activating capacities of DCs, we compared stimuli-responsive
to nonresponsive polymersome NVs. To do so, we employed “AND
gate” multiresponsive (MR) amphiphilic block copolymers that
decompose only in response to the combination of chemical cues present
in the environment of the intracellular compartments in antigen cross-presenting
DCs: low pH and high reactive oxygen species (ROS) levels. After being
unmasked by ROS, pH-responsive side chains are exposed and can undergo
a charge shift within a relevant pH window of the intracellular compartments
in antigen cross-presenting DCs. NVs containing the model antigen
Ovalbumin (OVA) and the iNKT cell activating adjuvant α-Galactosylceramide
(α-Galcer) were fabricated using microfluidics self-assembly.
The MR NVs outperformed the nonresponsive NV in vitro, inducing enhanced
classical- and cross-presentation of the OVA by DCs, effectively activating
CD8+, CD4+ T cells, and iNKT cells. Interestingly, in vivo, the nonresponsive
NVs outperformed the responsive vaccines. These differences in polymersome
vaccine performance are likely linked to the kinetics of cargo release,
highlighting the crucial chemical requirements for successful cancer
nanovaccines.