Bioenergetic-active hybrid nanovesicles empower tumor associated macrophages phagocytosis for cancer immunotherapy.

Bioenergy critically empowers cytoskeletal remodeling, which is essential for tumor-associated macrophages (TAMs) to engulf cancer cells. Consequently, engineering a bioenergetic-active nanomaterial to enhance TAM phagocytosis represents a promising strategy for cancer immunotherapy. Here, we develop a hybrid membrane-derived biomimetic nanovesicle loaded with paeonol (PAE) liposomes that exhibits capabilities for bioenergetic activation, TAM reprogramming, and TAM targeting. This nanovesicle, named PAE@mBG, utilizes bacterial ghosts (BGs) as a key component of its shell structure. BGs not only repolarize M2-like TAMs to the M1-like phenotype via their pathogen-associated molecular patterns, but also provide a hollow structure for efficient PAE loading. The PAE in PAE@mBG inhibits the AKT/mTOR pathway to induce mitophagy, thus enhancing ATP levels. This elevated ATP promotes F-actin polymerization and cytoskeletal remodeling, as evidenced by increased F-actin intensity and filament length, ultimately improving TAM phagocytosis. Furthermore, PAE@mBG efficiently targets TAMs through its hybrid membrane, which integrates BGs with M2pep-peptide-modified macrophage membranes possessing capabilities of innate tumor-homing and specific M2 macrophage targeting. Our findings demonstrate that PAE@mBG efficiently targets TAMs and enhances phagocytosis through bioenergetic activation and M2-to-M1 phenotype reprogramming, thereby triggering both innate and adaptive immunity for lung cancer immunotherapy.