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Abstract
Liposomal spherical nucleic acids (L-SNAs) show significant promise as cancer immunotherapeutics. L-SNAs are highly modular nanoscale assemblies defined by a dense, upright radial arrangement of oligonucleotides around a liposomal core. Herein, we establish a set of L-SNA design rules by studying the biological and immunological properties of L-SNAs as a function of liposome composition. To achieve this, we synthesized liposomes where the lipid phosphatidylcholine headgroup was held constant, while the diacyl lipid tail chain length and degree of saturation were varied, using either 1,2-dioleylphosphatidylcholine (DOPC), 1,2-dimyristoyl-phosphatidylcholine (DMPC), 1,2-dipalmitoylphosphatidylcholine (DPPC), or 1,2-distearoyl-phosphatidylcholine (DSPC). These studies show that the identity of the constituent lipid dictates the DNA loading, cellular uptake, serum stability, in vitro immunostimulatory activity, and in vivo lymph node accumulation of the L-SNA. Furthermore, in the 4T1 mouse model of triple-negative breast cancer (TNBC), the subcutaneous administration of immunostimulatory L-SNAs synthesized with DPPC significantly decreases the production of lung metastases and delays tumor growth as compared to L-SNAs synthesized using DOPC, due to the enhanced stability of L-SNAs synthesized with DPPC over those synthesized with DOPC. Moreover, the inclusion of cell lysates derived from Py8119 TNBC cells as antigen sources in L-SNAs leads to a significant increase in antitumor efficacy in the Py8119 model when lysates are encapsulated in the cores of L-SNAs synthesized with DPPC rather than DOPC, presumably due to increased codelivery of adjuvant and antigen to dendritic cells in vivo. This difference is further amplified when using lysates from oxidized Py8119 cells as a more potent antigen source, revealing synergy between the lysate preparation method and liposome composition in synthesizing immunotherapeutic L-SNAs. Together, this work shows that the biological properties and immunomodulatory activity of L-SNAs can be modulated by exchanging liposome components, providing another handle for the rational design of nanoscale immunotherapeutics.
Highlights
Liposomal spherical nucleic acids (L-SNAs) show significant promise as cancer immunotherapeutics
Following overnight incubation with DNA that is doubly functionalized with cholesterol and Cy5 (Table S1, entry 1) at T > TC for all lipids, colloidally stable L-SNAs formed from all liposome scaffolds
Förster resonance energy transfer (FRET)-capable L-SNAs were incubated in 10% fetal bovine serum (FBS) at 37 °C, and their stability was evaluated as a function of the decrease in FRET signal over time (Figure S2)
Summary
To assess the effect of liposome composition on the properties of L-SNAs, 80 nm liposomes comprised of lipids with varying. The administration of CpG-1826 in the 4T1 model of TNBC can suppress the spontaneous formation of lung metastases, as a form of “adjuvant-only” immunotherapy.[40,41] to evaluate whether L-SNA stability and in vitro immunostimulatory activity correlated with in vivo outcomes, the activity of DOPC-SNAs was compared to DPPC-SNAs in the 4T1 mouse model (Figure 4). DPPC-OxLys-SNAs significantly suppressed tumor growth over the duration of the study (Figure 5c), while DOPC-OxLys-SNAs were ineffective at these doses of DNA and lysate These data indicate that the effects of the lysate preparation method and L-SNA stability are synergistic, a trend which becomes clearer when the study end point for all DPPC-based L-SNAs is compared (Figure 5d). While DPPC-SNAs are ineffective at reducing tumor growth in the Py8119 model, the inclusion of lysates into the L-SNA (DPPC-Lys-SNAs) renders these materials effective, and maximum antitumor efficacy is observed when lysates from oxidized cells are used as the antigen sources (DPPC-OxLys-SNAs), revealing the importance of both the antigen processing method and liposome stability in these constructs
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