## 4 Nanodelivery Platform for Vaccine
### Lipid Nanoparticles (LNPs)  
Liposomes are the first LNPs to appear and have a bilayer vesicle structure [123], consisting mainly of phospholipids and cholesterol, which form a solid framework that is amphiphilic. The incorporation of cholesterol reduces the fluidity of liposome membranes and the permeability of aqueous molecules, increasing the stability of lipids in body fluids. Since the 1990s with the introduction of doxorubicin (Doxil(tm)) liposomes, the first nanomedicine for clinical oncology treatment, liposomal anticancer drugs have been now widely used in anticancer therapy [124], and liposomes can be used as a platform for delivering vaccines, releasing antigens in a controlled and slow manner, and inducing immune responses [125]. The shape, size, and surface charge of liposomes are important factors affecting immunoreactivity. Optimization of liposomes by changing the membrane composition and employing modifications with different moieties can be achieved to target vaccines actively or passively to different cellular and tissue sites. Modification of liposomes with a pH-sensitive polymer (ChexPG-PE) and a TLR2 ligand (h11c) can serve as a tool for neoantigen vaccine transport. The modified liposomal vaccine (h11c-Chex) enhanced the target activation of DCs and inhibited tumor growth [126]. The design of liposomal nanoparticle platforms responsive to the acidic tumor microenvironment enables controlled delivery and release of neoantigens. Flexible nanoplatform ratios also reduce systemic cytotoxicity while maintaining efficacy. Cancer immunotherapy response could be enhanced by combination with immune checkpoint blockers (Figure 3) [127]. Figure 3: (**A**) LN-IMQ can encapsulate neoantigens induced by chemotherapeutic agents, with encapsulation rates up to 67.4%. (**B**) LN-IMQ-derived vaccines are able to trigger potent antitumor responses by modifying the tumor microenvironment in combination with ICB. Reprinted with permission from ref. [127]. Copyright 2023 American Chemical Society. Notes: red up arrow means activation or upward adjustment. In addition to using modifications to alter the properties of liposomes, researchers have also combined tumor vaccines and photothermal therapy or ICIs to improve antitumor efficacy. [PERSON] et al. prepared an FA-TSL/AuNCs/SV nanoplatform by integrating folic acid-modified thermal-sensitive liposomes (FA-TSL) as the shell and simvastatin (SV) adjuvant-loaded Au nanocages (AuNCs) as the cores. The liposomes can be engulfed by tumor cells more effectively due to FA decoration. Tumor-derived protein antigens (TDPAs) were released due to photothermal treatment (PTT) mediated by AuNCs, which was further captured by AuNCs/SV, and formed the in situ recombinant vaccine (AuNCs/SV/TDPAs). AuNCs/SV/TDPAs could efficiently transport to draining LNs owing to the hyperthermal-induced vasodilation effect and small particle size, achieving co-delivery of antigens and adjuvant for the initiation of specific T cell response [77]. In a study, a colon cancer cell-derived neoantigen peptide, Adpgk, was encapsulated into liposomes (Adpgk-BPQDs-liposome) along with black phosphorus quantum dots, and the combination of ICIs blocked tumor progression [57]. Lipoproteins are a class of particles that act as transporters in the bloodstream in vivo and can be categorized mainly into high-density lipoproteins and low-density lipoproteins. Lipoproteins are a highly desirable delivery platform, highly biocompatible, and suitable for modification in a variety of ways to target specific tissues [128]. Synthetic high-density lipoprotein (sHDL) presents a promising future as a new liposome-based platform in neoantigen delivery systems. [PERSON] et al. developed nanodiscs of sHDL based on phospholipids and ApoA1 mimetic peptides. sHDL is highly secure, has multiple loading sites, and is very small in size (~10 nm) [96]. Cholesterol-CpG and neoantigen peptides are extremely easy to assemble into sHDL nanodiscs, presenting a homogeneous, stable, and ultra-small state.