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Targeted immunomodulation through biomolecule-based nanostructures, especially to dendritic cells (DCs), holds great promise for effective cancer therapy. However, construction of high-performance agonist by mimicking natural ligand to activate immune cell signaling is a great challenge so far. Here, a peptide-based nanoagonist toward CD40 (PVA-CD40) with preorganized interfacial topological structure that activates lymph node DCs efficiently and persistently, achieving amplified immune therapeutic efficacy is described. The on-site fabrication of PVA-CD40 is realized through the click conjugation of two functional peptides including the "CD40 anchoring arm" and the "assembly-driving motor." The resultant polyvalent interface rapidly triggers the receptor oligomerization and downstream signaling. Strikingly, one shot administration of PVA-CD40 elicits maturation period of DCs up to 2.3-fold comparing to that of CD40 antibody. Finally, combining the PVA-CD40 with anti-PD-1 antibody results in subsequent inhibition of tumor growth in both B16F10 and 4T1 mice tumor models with survival rate up to 37%, while none of the mice survives in the clinically relevant CD40 mAb and anti-PD-1 combination-treated group. It is envisioned that the fabrication of antibody-like superstructures in vivo provides an efficient platform for modulating the duration of immune response to achieve optimal therapeutic efficacy.

One of the major challenges of immune checkpoint blockade (ICB) is the poor penetration of antibody for solid tumor treatment. Herein, peptides with deeper penetration capability are used to develop a click reaction-assisted peptide immune checkpoint blockade (CRICB) strategy that could in situ construct assemblies, enabling enhanced accumulation and prolonged PD-L1 occupancy, ultimately realizing high-performance tumor inhibition. First, the free DBCO-modified targeting peptide (TP) efficiently recognizes and binds PD-L1 in a deep solid tumor. Upon a reagent-free click reaction with a subsequently introduced azide-tethered assembled peptide (AP), the click reaction results in spontaneous self-aggregation in situ with enhanced accumulation and prolonged occupancy. In addition, the penetration of TP-AP (121.2 ± 15.5 μm) is significantly enhanced compared with that of an antibody (19.9 ± 5.6 μm) in a solid tumor tissue. More importantly, significant immunotherapy effects and negligible side effects are observed in 4T1 and CT26 tumor-bearing mice models treated with TP-AP, suggesting the high-performance tumor inhibition attributed to the CRICB strategy. In summary, this CRICB strategy manifest the preferable effects of immune checkpoint blockade, thereby extending the biomedical application of assembling peptides.

Due to intrinsic and acquired chemo/radiotherapy-resistance, renal cell carcinoma shows limited therapeutic response to clinically utilized targeting drugs. Here a tumor-activated oncolytic peptide nanomachine is devised to selectively lysing tumor cell membrane without causing drug resistance. Specifically, in the acidic tumor microenvironment, the oncolytic peptide nanomachine automatically activated through morphologically transformation from nanoparticles to nanofibrils with restoring α-helical conformation, which physically bind to tumor cell membrane with multiple (spatially correlated and time-resolved) interactions and subsequently lyse local cell membrane. The IC

Cancer vaccines have exhibited immense potential in cancer treatment. Through activating the host's immune system, vaccines stimulate extensive functional T cells to eliminate cancer. However, the therapeutic efficacy of cancer vaccines is limited by their inferior lymph node delivery and inadequate uptake of dendritic cells. Herein, we propose an in situ phase transitional strategy on vaccine manufacturing to maximally enhance lymph node drainage while ensuring adequate dendritic cell uptake. The phase transitional vaccines, with dynamic size modulation property, retain a small size (24.4 ± 3.1 nm) during lymph node draining then transform into larger particles (483.0 ± 41.6 nm) on-site by external signal input. Results show that this strategy induced rapid and robust immune response in a mouse melanoma tumor model. Furthermore, a stronger humoral immune response was observed in mice when immunized with MHC-II restricted antigen, which demonstrated that lymph node-targeted cancer vaccine delivery could be effectively manipulated through dynamic size modulation.

Cellular immunotherapeutics aim to employ immune cells as anticancer agents. Ex vivo engineering of dendritic cells (DCs), the initial role of an immune response, benefits tumor elimination by boosting specific antitumor responses. However, directly activating DCs in vivo is less efficient and therefore quite challenging. Here, we designed a nanoactivator that manufactures DCs through autophagy upregulating in vivo directly, which lead to a high-efficiency antigen presention of DCs and antigen-specific T cells generation. The nanoactivator significantly enhances tumor antigen cross-presentation and subsequent T cell priming. Consequently, in vivo experiments show that the nanoactivators successfully reduce tumor growth and prolong murine survival. Taken together, these results indicate in situ DCs manipulation by autophagy induction is a promising strategy for antigen presentation enhancement and tumor elimination.

Cationic therapeutic peptides have received widespread attention due to their excellent antibacterial and antitumor properties. However, most of these peptides have undesirable delivery efficiency and high hemolytic toxicity due to the positively charged α-helix structure containing many lysine and arginine, which may restrict its in vivo applications. Herein, a conformationally transformed therapeutic peptide Pep-HCO3 modified with bicarbonates on guanidine groups is designed. Such a design allows Pep-HCO3 ((nap-RAGLQFPVGRLLRRLLRRLLR) nHCO3 ) to self-assemble into nanoparticles (NP-Pep) due to disrupting helix folding and the formation of intermolecular hydrogen bonding between bicarbonates and guanidine groups. When pH is from 7.4 to 6.5 at the tumor sites, guanidine bicarbonate can be hydrolyzed to form CO2 and guanidine groups, resulting in the disassembling of the NP-Pep into monomers α-Pep with a positively charged α-helix structure. In vivo, NP-Pep not only inhibits the tumor growth of xenografted mice with a twofold enhanced inhibition rate compared with α-Pep treatment group, but also significantly reduces the hemolytic toxicity by responding to the pH of tumor microenvironment. Therefore, the strategy of conformational transition-triggered disassembly of nanoparticles allows efficient delivery of cationic therapeutic peptides and lowering the hemolytic toxicity, which may provide an avenue for developing high-performance cationic peptide in vivo applications.

The rapid development of nanobiotechnology has enabled progress in therapeutic cancer vaccines. These vaccines stimulate the host innate immune response by tumor antigens followed by a cascading adaptive response against cancer. However, an improved antitumor immune response is still in high demand because of the unsatisfactory clinical performance of the vaccine in tumor inhibition and regression. To date, a complicated tumor immunosuppressive environment and suboptimal design are the main obstacles for therapeutic cancer vaccines. The optimization of tumor antigens, vaccine delivery pathways, and proper adjuvants for innate immune response initiation, along with reprogramming of the tumor immunosuppressive environment, is essential for therapeutic cancer vaccines in triggering an adequate antitumor immune response. In this review, we aim to review the challenges in and strategies for enhancing the efficacy of therapeutic vaccines. We start with the summary of the available tumor antigens and their properties and then the optimal strategies for vaccine delivery. Subsequently, the vaccine adjuvants focused on the intrinsic adjuvant properties of nanostructures are further discussed. Finally, we summarize the combination strategies with therapeutic cancer vaccines and discuss their positive impact in cancer immunity.

The fabrication of functional assemblies with defined structures through controllable molecular packing under physiological conditions is challenging. Here, modularly designed peptide-cyanine conjugates that intracellularly self-assembly into 1D columnar superstructures with controlled cyanine aggregation were designed, and they exhibit distinct imaging or photothermal properties. The peptide backbone is cleaved by caspase-3/7 after entering the cells. Then the self-assembled residue, with a double cyanine substitution (Pr-2Cy), forms a P helical column in which H-aggregated cyanine dyes show 3.4-fold photothermal conversion efficiency compared to free ones. The self-assembled residue with a single cyanine substitution (Pr-1Cy) forms a loose column, in which cyanine dyes with undefined structure have a fluorescence quantum yield of up to 9.5 % (emission at 819 nm in H2 O). This work provides a simple way to modify in vivo self-assembled peptides with functional molecules for achieving desired bio-applications.