Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy. Nanovaccines may improve efficacy but have rarely been clinically translated. By conjugating molecular vaccines with Evans blue (EB) into albumin-binding vaccines (AlbiVax), here we develop clinically promising albumin/AlbiVax nanocomplexes that self-assemble in vivo from AlbiVax and endogenous albumin for efficient vaccine delivery and potent cancer immunotherapy. PET pharmacoimaging, super-resolution microscopies, and flow cytometry reveal almost 100-fold more efficient co-delivery of CpG and antigens (Ags) to lymph nodes (LNs) by albumin/AlbiVax than benchmark incomplete Freund’s adjuvant (IFA). Albumin/AlbiVax elicits ~10 times more frequent peripheral antigen-specific CD8+ cytotoxic T lymphocytes with immune memory than IFA-emulsifying vaccines. Albumin/AlbiVax specifically inhibits progression of established primary or metastatic EG7.OVA, B16F10, and MC38 tumors; combination with anti-PD-1 and/or Abraxane further potentiates immunotherapy and eradicates most MC38 tumors. Albumin/AlbiVax nanocomplexes are thus a robust platform for combination cancer immunotherapy.

Vaccines hold tremendous potential for cancer immunotherapy by treating the immune system. Subunit vaccines, including molecular adjuvants and cancer-associated antigens or cancer-specific neoantigens, can elicit potent antitumor immunity. However, subunit vaccines have shown limited clinical benefit in cancer patients, which is in part attributed to inefficient vaccine delivery. In this Perspective, we discuss vaccine delivery by synthetic nanoparticles or naturally derived nanoparticles for cancer immunotherapy. Nanovaccines can efficiently codeliver adjuvants and multiepitope antigens into lymphoid organs and into antigen-presenting cells, and the intracellular release of vaccine and cross-presentation of antigens can be fine-tuned via nanovaccine engineering. Aside from peptide antigens, antigen-encoding mRNA for cancer immunotherapy delivered by nanovaccine will also be discussed.

A rapid and efficient approach for the preparation and modification of a versatile class of functional polymer nanoparticles has been developed, for which the entire engineering process from small molecules to polymers to nanoparticles bypasses typical slow and inefficient procedures, and rather employs a series of steps that capture fully the “click” chemistry concepts that have greatly facilitated the preparation of complex polymer materials over the past decade. The construction of various nanoparticles with functional complexity from a versatile platform is a challenging aim to provide materials for fundamental studies and also optimization toward a diverse range of applications. In this paper, we demonstrate the rapid and facile preparation of a family of nanoparticles with different surface charges and functionalities based on a biodegradable polyphosphoester block copolymer system. From a retrosynthetic point of view, the non-ionic, anionic, cationic and zwitterionic micelles with hydrodynamic diameters between 13 nm to 21 nm and great size uniformity were quickly formed by suspending, independently, four amphiphilic diblock polyphosphoesters into water, which were functionalized from the same parental hydrophobic-functional AB diblock polyphosphoester by “click” type thiol-yne reactions. The well-defined (PDI < 1.2) hydrophobic-functional AB diblock polyphosphoester was synthesized by an ultrafast (< 5 min) organocatalyzed ring-opening polymerization in a two-step, one-pot manner with the quantitative conversions of two kinds of cyclic phospholane monomers. The whole programmable process starting from small molecules to nanoparticles could be completed within 6 h, as the most rapid approach for the anionic and non-ionic nanoparticles, although the cationic and zwitterionic nanoparticles required ca. 2 days due to purification by dialysis. The micelles showed high biocompatibility, with even the cationic micelles exhibiting a 6-fold lower cytotoxicity toward RAW 264.7 mouse macrophage cells, as compared to the Lipofectamine® commercial transfection agent.