Immunotherapy is revolutionizing the clinical management of patients with different cancer types by sensitizing autologous or allogenic immune cells to the tumor microenvironment which eventually leads to tumor cell lysis without rapidly killing normal cells. Although immunotherapy has been widely demonstrated to be superior to chemotherapies, only a few populations of patients with specific cancer types respond to such treatment due to the failure of systemic immune activation. In addition, severe immune-related adverse events are rapidly observed when patients with very few responses are given higher doses of such therapies. Recent advances of lipid-based nanoparticles (NPs) development have made it possible to deliver not only small molecules but also mRNAs to achieve systemic anticancer immunity through cytotoxic immune cell activation, checkpoint blockade, and chimeric antigen receptor cell therapies, etc. This review summarized recent development and applications of LNPs in anticancer immunotherapy. The diversity of lipid-based NPs would encapsulate payloads with different structures and molecular weights to achieve optimal antitumor immunity through multiple mechanisms of action. The discussion about the components of lipid-based NPs and their immunologic payloads in this review hopefully shed more light on the future direction of anticancer immunotherapy.

The ability of lipid nanoparticles (LNPs) to deliver nucleic acids have shown a great therapeutic potential to treat a variety of diseases. Here, an optimized formulation of QTsome lipid nanoparticles (QTPlus) is utilized to deliver an anti‐miR‐21 (AM21) against cancer. The miR‐21 downstream gene regulation and antitumor activity is evaluated using mouse and human cancer cells and macrophages. The antitumor activity of QTPlus encapsulating AM21 (QTPlus‐AM21) is further evaluated in combination with erlotinib and atezolizumab (ATZ). QTPlus‐AM21 demonstrates a superior miR‐21‐dependent gene regulation and eventually inhibits A549 non‐small cell lung cancer growth in vitro. QTPlus‐AM21 further induces chemo‐sensitization of A549 cells to erlotinib with a combination index of 0.6 in inhibiting A549 cell growth. When systemically administers to MC38 tumor‐bearing mouse model, QTPlus‐AM21 exhibits an antitumor immune response with over 80% tumor growth inhibition (TGI%) and over twofold and fourfold PD‐1 and PD‐L1 upregulation in tumors and spleens. The combination therapy of QTPlus‐AM21 and ATZ further shows a higher antitumor response (TGI% over 90%) and successfully increases M1 macrophages and CD8 T cells into TME. This study provides new insights into the antitumor mechanism of AM21 and shows great promise of QTPlus‐AM21 in combination with chemotherapies and immunotherapies.