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malignant cells. Immune checkpoint inhibitors (ICIs), such as anti-PD1 and anti-CTLA4 antibodies, are among the most successful immunotherapy modalities that have shown therapeutic benefits in various types of cancers, from melanoma to lung cancer. [1] However, only a minority of cancer patients are responsive to ICIs therapy, depending on their immunophenotype and cancer genotype. [2] Chemo-immunotherapy is a combination of "standard-of-care" chemotherapy with immunotherapy, mostly ICIs such as nivolumab and pembrolizumab that shows therapeutic benefit in the clinic and success in phase III trials. [3] Yet, many patients are still poorly responsive to this combination therapy and nanotherapeutics could be a novel strategy for the improvement of chemo-immunotherapy.The tumor immune microenvironment is enriched with various immune cells from myeloid cells to lymphocytes. Tumor myeloid cells including monocytes and macrophages are recruited by the inflamed cancer cell niche and paradoxically induce "immunosuppressive" status in solid tumors. [2b,4] In particular, tumor-associated macrophages (TAM) that are originated from tumor-infiltrated monocytes [5] directly remodel the tumor immune microenvironment by physically impeding infiltration of cytotoxic CD8 + T lymphocytes and Chemo-immunotherapy is a combination of "standard-of-care" chemotherapy with immunotherapy and it is considered the most advanced therapeutic modality for various types of cancers. However, many cancer patients still poorly respond to current regimen of chemo-immunotherapy and suggest nanotherapeutics as a boosting agent. Recently, heme oxygenase-1 (HO1) is shown to act as an immunotherapeutic molecule in tumor myeloid cells, in addition to general chemoresistance function in cancer cells suggesting that HO1-targeted therapeutics can become a novel, optimal strategy for boosting chemo-immunotherapy in the clinic. Currently the available HO1-inhibitors demonstrate serious adverse effects in clinical use. Herein, tumor myeloid cell-and cancer cell-dual targeted HO1-inhibiting lipid nanotherapeutic boost (T-iLNTB) is developed using RNAiloaded lipid nanoparticles. T-iLNTB-mediated HO1-inhibition sensitizes cancer cells to "standard-of-care" chemotherapeutics by increasing immunogenic cell death, and directly reprograms tumor myeloid cells with distinguished phenotype. Furthermore, tumor myeloid cell reprogramming by T-iLNTB induces CD8 + cytotoxic T cell recruitment, which drives "Cold-to-Hot" transition and correlates with improved responsiveness to immune checkpoint inhibitor in combination therapy. Finally, ex vivo study proves that HO1-inhibition directly affects tumor macrophage differentiation. This study demonstrates the potential of T-iLNTB as a novel therapeutic modality for boosting chemo-immunotherapy.

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Ionizable lipid-based nanoparticles (LNPs) are the most advanced non-viral drug delivery systems for RNA therapeutics and vaccines. However, cell type-specific, extrahepatic mRNA delivery is still a major hurdle, hampering the development of novel therapeutic modalities. Herein, a novel ionizable lipid library is synthesized by modifying hydrophobic tail chains and linkers. Combined with other helper lipids and utilizing a microfluidic mixing approach, stable LNPs are formed. Using Luciferase-mRNA, mCherry mRNA, and Cre mRNA together with a TdTomato animal model, superior lipids forming LNPs for potent cell-type specific mRNA delivery are identified. In vitro assays concluded that combining branched ester tail chains with hydroxylamine linker negatively affects mRNA delivery efficiency. In vivo studies identify Lipid 23 as a liver-trophic, superior mRNA delivery lipid and Lipid 16 as a potent cell type-specific ionizable lipid for the CD11b hi macrophage population without an additional targeting moiety. Finally, in vivo mRNA delivery efficiency and toxicity of these LNPs are compared with SM-102-based LNP (Moderna's LNP formulation) and are shown to be cell-specific compared to SM-102-based LNPs. Overall, this study suggests that a structural combination of tail and linker can drive a novel functionality of LNPs in vivo.