Neoantigen vaccines have been enthusiastically pursued for personalized cancer immunotherapy while vast majority of neoantigens have no or low immunogenicity. Here, a bi-adjuvant neoantigen nanovaccine (banNV) that codelivered a peptide neoantigen (Adpgk) with two adjuvants [Toll-like receptor (TLR) 7/8 agonist R848 and TLR9 agonist CpG] was developed for potent cancer immunotherapy. Specifically, banNVs were prepared by a nanotemplated synthesis of concatemer CpG, nanocondensation with cationic polypeptides, and then physical loading with hydrophobic R848 and Adpgk. The immunogenicity of the neoantigen was profoundly potentiated by efficient codelivery of neoantigen and dual synergistic adjuvants, which is accompanied by reduced acute systemic toxicity. BanNVs sensitized immune checkpoint programmed death receptor 1 (PD-1) on T cells, therefore, a combination of banNVs with aPD-1 conspicuously induced the therapy response and led to complete regression of 70% neoantigenspecific tumors without recurrence. We conclude that banNVs are promising to optimize personalized therapeutic neoantigen vaccines for cancer immunotherapy. A bi-adjuvant nanovaccine that potentiates immunogenicity of neoantigen for combination immunotherapy of colorectal cancer. Sci. Adv. 6, eaaw6071 (2020).

Cancer immunotherapy modulates and leverages the host immune system to treat cancer. The past decade has witnessed historical advancement of cancer immunotherapy. A myriad of approaches have been explored to elicit or augment anticancer innate immunity and/or adaptive immunity. Recently, activation of stimulator of interferon (IFN) genes (STING), an intracellular receptor residing in the endoplasmic reticulum, has shown great potential to enhance antitumor immunity through the induction of a variety of pro-inflammatory cytokines and chemokines, including type I IFNs. A number of natural and synthetic STING agonists have been discovered or developed, and tested in preclinical models and in the clinic for the immunotherapy of diseases such as cancer and infectious diseases. Cyclic dinucleotides (CDNs), such as cyclic dimeric guanosine monophosphate (c-di-GMP), cyclic dimeric adenosine monophosphate (c-di-AMP), and cyclic GMP-AMP (cGAMP), are a class of STING agonists that can elicit immune responses. However, natural CDNs are hydrophilic small molecules with negative charges and are susceptible to enzymatic degradation, leading to low bioavailability in target tissues yet unwanted toxicities and narrow therapeutic windows. Drug delivery systems, coupled with nucleic acid chemistry, have been exploited to address these challenges. Here, we will discuss the underlying immunological mechanisms and approaches to STING activation, with a focus on the delivery of STING agonists, for cancer immunotherapy.

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Polysaccharide hydrogels are widely used in tissue engineering because of their superior biocompatibility and low immunogenicity. However, many of these hydrogels are unrealistic for practical applications as the cost of raw materials is high, and the fabrication steps are tedious. This study focuses on the facile fabrication and optimization of agarose-polydopamine hydrogel (APG) scaffolds for skin wound healing. The first study objective was to evaluate the effects of polydopamine (PDA) on the mechanical properties, water holding capacity and cell adhesiveness of APG. We observed that APG showed decreased rigidity and increased water content with the addition of PDA. Most importantly, decreased rigidity translated into significant increase in cell adhesiveness. Next, the slow biodegradability and high biocompatibility of APG with the highest PDA content (APG3) was confirmed. In addition, APG3 promoted full-thickness skin defect healing by accelerating collagen deposition and promoting angiogenesis. Altogether, we have developed a straightforward and efficient strategy to construct functional APG scaffold for skin tissue engineering, which has translation potentials in clinical practice.