Potent cancer therapy by liposome microstructure tailoring with active-to-passive targeting and shell-to-core thermosensitive features.

ABSTRACT

Liposomes have been widely studied as drug carriers for clinical application, and the key issue is how to achieve effective delivery through targeting strategies. Even though certain cell-level targeting or EPR effect designs have been developed, reaching sufficient drug concentration in intracellular regions remains a challenge due to the singularity of functionality. Herein, benefiting from the unique features of tumor from tissue to cell, a dual-thermosensitive and dual-targeting liposome (DTSL) was creatively fabricated through fine microstructure tailoring, which holds intelligent both tissue-regulated active-to-passive binding and membrane-derived homologous-fusion (HF) properties. At the micro level, DTSL can actively capture tumor cells and accompany the enhanced HF effect stimulated by self-constriction, which achieves a synergistic promotion effect targeting tissues to cells. As a result, this first active-then passive targeting process makes drug delivery more accurate and effective, and after dynamic targeting into cells, the nucleus of DTSL undergoes further thermally responsive contraction, fully releasing internal drugs. In vivo experiments showed that liposomes with dual targeting and dual thermosensitive features almost completely inhibited tumor growth. Summarized, these results provide a reference for a rational design and microstructural tailoring of the liposomal co-delivery system of drugs, suggesting that active-to-passive dual-targeting DTSL can function as a new strategy for cancer treatment.