Intracellular Nanoparticle Formation and Hydroxychloroquine Release for Autophagy‐Inhibited Mild‐Temperature Photothermal Therapy for Tumors

Abstract Mild‐temperature photothermal therapy (PTT) of tumors has been intensively explored and adopted in preclinical/clinical trials in recent years. Nevertheless, tumor thermoresistance significantly compromises the therapeutic efficacy of mild‐temperature PTT, and therefore, the extra addition of anti‐thermoresistance agent is needed. Herein, by rational design of a peptide‐hydroxychloroquine (HCQ) conjugate Cypate‐Phe‐Phe‐Lys(SA‐HCQ)‐Tyr(H 2 PO 3 )‐OH (Cyp‐HCQ‐Yp), a “smart” strategy of enzyme‐triggered simultaneously intracellular photothermal nanoparticle formation and HCQ release is proposed for autophagy‐inhibited mild‐temperature PTT of tumor. In vitro results show that, under sequential catalysis of enzymes alkaline phosphatase and carboxylesterase, Cyp‐HCQ‐Yp is converted to Cypate‐Phe‐Phe‐Lys(SA)‐Tyr‐OH (Cyp‐Y) which self‐assembles into its nanoparticle Cyp‐NP and HCQ is released from Cyp‐HCQ‐Yp. By comparing with two control agents, it is validated that the exceptional therapeutic effect of Cyp‐HCQ‐Yp on tumor in vivo is achieved by its dual‐enzyme‐controlled intracellular nanoparticle formation and autophagy inhibition in tumors.