Supramolecular Macrophage‐Liposome Marriage for Cell‐Hitchhiking Delivery and Immunotherapy of Acute Pneumonia and Melanoma

Abstract As many diseases are related to inflammation, the inflammatory tropism of immune cells may bring cell‐hitchhikers directly to the disease tissues in a highly targeted manner. The current cell‐hitchhiking strategies rely on either cellular internalization or covalent surface conjugation, which often affects the physiological function of transporting cells. Herein, a cell‐friendly, host‐guest chemistry mediated macrophage‐liposome conjugate (M‐L) is developed for extremely stable cell‐hitchhiking drug delivery. M‐L is prepared via simple supramolecular “hand‐holding” and marriage between cucurbit[7]uril (CB[7]) and adamantane, respectively anchored on the surface of the macrophage and liposome, which demonstrates targeted accumulation in the inflamed lung and effective therapy of acute pneumonia in mice when loaded with quercetin. Upon loading toxic chemotherapeutic agents (such as doxorubicin and oxaliplatin), M‐L carries the payloads to the inflammatory cancer tissue and significantly enhances the chemoimmunotherapy of melanoma in mice. Fundamentally, this CB[7]‐based supramolecular M‐L conjugation strategy shows negligible effects on the migratory and invasive behaviors of macrophages. In vivo pathological analysis of the inflammatory tissues in mice after treatment with M‐L further suggests that macrophage and liposomes are delivered together hand in hand. This CB[7]‐based, supramolecular cell‐conjugation strategy potentially addresses the key challenges faced by the current cell‐based delivery systems.