Figure 7. Proposed mechanism of targeting TAFs for in situ engineering.

A. Plasmid encoding secretable TRAIL protein is condensed with protamine and further encapsulated into PEGylated liposomes coating with anisamide targeting motif (LPD). Diagram of the p-sTRAIL LPD is shown. B. LPD is systemically delivered to tumor region, and then extravasated from blood vessel due to the EPR effect. In most desmoplastic tumors, a thick layer of fibroblasts wraps around the blood vessel. Tumor-associated fibroblasts (TAFs) are the major cells taken up the targeted LPD. C. sTRAIL protein is synthesized by TAFs and diffuses to the neighboring tumor cells. Apoptotic tumor cells reciprocally failed to activate local fibroblasts, reverting the TAFs to normal fibroblasts (NFs). NFs can suppress tumor growth on one end, remodel the TME, and increase the penetration of a second wave chemotherapeutic NPs on the other. Collectively, this multi-wave therapy can induce potent growth inhibition of the desmoplastic tumors.