LL37 is a cationic, amphipathic host-defense peptide (HDP) with dual antimicrobial and immunomodulatory properties essential to immune defense against microbial pathogens. However, LL37 has recently been identified as an autoantigen that breaks immune tolerance to self-nucleic acids via Toll-like receptors (TLRs) in psoriasis. At present, the mechanism by which LL37 interacts with self-dsDNA or dsRNA to modulate TLRs is poorly understood. Here, we study the immunomodulatory behavior of LL37 from the perspective of “Janus” self-assembly, which can organize low-symmetry subunits into diverse nanostructures. We examined the supramolecular structures formed between prototypical helical HDPs and DNA using synchrotron small angle X-ray scattering (SAXS) and molecular modeling. We find that LL37 self-assembles into cationic protofibrils with hydrophobic interiors, which in turn nucleate ordered complexes with spatially-periodic DNA ligands. Interestingly, LL37-DNA complexes trigger strong immune responses in plasmacytoid dendritic cells (pDCs) by driving receptor clustering and multivalent binding of TLR9 to periodic DNA ligands within the nanocrystal, thereby amplifying TLR9-mediated inflammation. In cognate work, we find that this paradigm is general to other innate immune receptors. LL37 organizes dsRNA into spatially-periodic nanocrystalline immune complexes to amplify TLR3-mediated inflammation in keratinocytes. LL37-dsRNA complexes have inter-RNA spacings well-matched with the steric size of TLR3, enabling multivalent binding of clustered TLR3 to periodic dsRNA ligands. These findings suggest that LL37-nucleic acid nanocrystals exacerbate inflammation in psoriasis through different parallel pathways in dendritic cells and keratinocytes. Our findings unveil potential therapeutic strategies to disrupt inflammation in psoriasis.