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Double-stranded RNA (dsRNA) can induce potent production of pro-inflammatory cytokines in normal human epidermal keratinocytes (NHEK) by binding to endosomal Toll-like receptor-3 (TLR3). It is also known that the cationic human antimicrobial peptide LL37 forms electrostatic immune complexes with self-dsRNA to hyperactivate TLR3 in psoriatic keratinocytes. Here, we combine X-ray scattering experiments and computer simulations with measurements of NHEK cytokine production to elucidate a selection rule for cationic molecules that electrostatically condense dsRNA and activate TLR3. TLR3 activation intimately depends on the inter-RNA spacing and repeat number of parallel dsRNA molecules in the liquid-crystalline self-assembled complexes. Complexes that present dsRNA at the optimal spacing can engage multiple TLR3 receptors simultaneously, driving receptor clustering, super-selective receptor …