CD44‐Specific A6 Short Peptide Boosts Targetability and Anticancer Efficacy of Polymersomal Epirubicin to Orthotopic Human Multiple Myeloma

Abstract Chemotherapy is widely used in the clinic though its benefits are controversial owing to low cancer specificity. Nanovehicles capable of selectively transporting drugs to cancer cells have been energetically pursued to remodel cancer treatment. However, no active targeting nanomedicines have succeeded in clinical translation to date, partly due to either modest targetability or complex fabrication. CD44‐specific A6 short peptide (KPSSPPEE) functionalized polymersomal epirubicin (A6‐PS‐EPI), which boosts targetability and anticancer efficacy toward human multiple myeloma (MM) in vivo, is described. A6‐PS‐EPI encapsulating 11 wt% EPI is small (≈55 nm), robust, reduction‐responsive, and easy to fabricate. Of note, A6 decoration markedly augments the uptake and anticancer activity of PS‐EPI in CD44‐overexpressing LP‐1 MM cells. A6‐PS‐EPI displays remarkable targeting ability to orthotopic LP‐1 MM, causing depleted bone damage and striking survival benefits compared to nontargeted PS‐EPI. Overall, A6‐PS‐EPI, as a simple and intelligent nanotherapeutic, demonstrates high potential for clinical translation.