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The objective of this dissertation is to develop novel nanomedicines against cancer using lipid-based nanoparticles to deliver small molecules, oligonucleotides, and messenger RNA (mRNA).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. In the present dissertation, we introduced the development of lipid-based nanoparticles (NPs) against cancer which could deliver not only small molecules but also mRNAs to achieve systemic anticancer immunity through cytotoxic immune cell activation, checkpoint blockade, and enhancing antitumor responses by traditional chemotherapies, etc. In chapter 1, we 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. In Chapter 2, we introduced a squalene-based nanoemulsion (NE) to deliver resiquimod (R848), a toll-like receptor (TLR) 7/8 agonist. The R848 NE was shown to be highly stable during long-term storage at 4 °C. R848 NE exhibited superior antitumor immunity when in combined with SD-101, a TLR9 agonist in vitro and in vivo. Furthermore, we also demonstrated that our squalene NE was able to co-load R848 and ivermectin (IVM). R848-IVM co-loaded NE exhibited long-term stability and reduced cytotoxicity by IVM. In vivo studies demonstrated that IVM significantly augments the ICD by upregulating Cd8a and releasing HMGB1 in tumor tissue, which could enhance R848-driven antitumor immunity. R848-IVM NE treatment showed strong antitumor activity with over 80% tumor growth inhibition, suggesting a potential combination therapy of systemic co-delivering IVM with TLR agonists against solid cancer. In Chapter 3, we developed a next-generation QTsome for nucleic acid delivery. QTsome is a lipid nanoparticle platform using a combination of quaternary amine and tertiary amine to facilitate drug delivery. Traditional QTsome can deliver small molecule-based chemotherapies to enhance its antitumor activity by increasing the half-life time in systemic fluid. By decreasing the cationic lipids and PEG lipids, increasing ionizable lipids, and selecting the optimal helper lipid and ionizable lipid, we demonstrated that our next-generation QTsome (QTPlus) is capable of gene delivery including oligonucleotides and mRNA. In Chapter 4, we developed an antisense oligonucleotide (ASO) against microRNA-21 and used QTPlus to enhance its antitumor activity in multiple tumor models. In combination with chemotherapy and immune-checkpoint blockade, our QTPlus-encapsulating ASO should superior antitumor responses in vivo. The discussion about the components of lipid-based NPs and their payloads in this dissertation hopefully sheds light on the future direction of cancer therapy.