Lipophilic siRNA targets albumin in situ and promotes bioavailability, tumor penetration, and carrier-free gene silencing

Significance Small interfering RNA (siRNA) has the capacity to silence traditionally undruggable targets, but in vivo delivery barriers limit clinical translation of siRNA, especially for nonhepatic targets such as solid tumors. Most delivery strategies for RNAi cancer therapies focus on synthetic nanocarriers, but their shortcomings include limited delivery to and variable distribution throughout the target site and low therapeutic indices due to nonspecific, carrier-associated toxicities. A diacyl lipid-modified siRNA can leverage albumin as an endogenous carrier, resulting in comprehensively enhanced pharmacokinetic properties that translate to greater quantity and homogeneity of tumor accumulation relative to nanocarriers. The albumin-binding siRNA conjugate strategy is synthetically simple and safe at high doses, and thus is a translatable and potentially transformative option for RNAi oncology therapies.