Bacterial and cancerous cell membrane fused liposome coordinates with PD-L1 inhibitor for cancer immunotherapy

Although tumor cell membranes with broad-spectrum antigens have been explored for cancer vaccines for decades,their relatively poor capacity to stimulate immune responses,especially cellular immune responses,has limited their application.Here,we presented a novel bacterial and cancerous cell membrane fusogenic liposome for co-delivering cell membrane-derived antigens and adjuvants.Meanwhile,a programmed death-ligand 1(PD-L1)inhibitor,JQ-1,was incorporated into the formulation to tackle the up-regulated PD-L1 expression of antigen-presenting cells(APCs)upon vaccination,thereby augmenting its anti-tumor efficacy.The fusogenic liposomes demonstrated significantly improved cellular uptake by APCs and effectively suppressed PD-L1 expression in bone marrow-derived dendritic cells(BMDCs)in vitro.Following subcutaneous vaccination,the nano-vaccines efficiently drained to the tumor-draining lymph nodes(TDLNs),and significantly inhibited PD-L1 expression of both dendritic cells(DCs)and macrophages within the TDLNs and tumors.As a result,the liposomal vaccine induced robust innate and cellular immune responses and inhibited tumor growth in a colorectal carcinoma-burden mouse model.In summary,the fabricated cell membrane-based fusogenic liposomes offer a safe,effective,and easily applicable strategy for tumor immunotherapy and hold potential for personalized cancer immunotherapy.

Single-shot AAV-vectored vaccine against SARS-CoV-2 with fast and long-lasting immunity

Due to the insufficient long-term protection and significant efficacy reduction to new variants of current COVID-19 vaccines,the epidemic prevention and control are still challenging.Here,we employ a capsid and antigen structure engineering(CASE)strategy to manufacture an adenoassociated viral serotype 6-based vaccine(S663V-RBD),which expresses trimeric receptor binding domain(RBD)of spike protein fused with a biological adjuvant RS09.Impressively,the engineered S663V-RBD could rapidly induce a satisfactory RBD-specific IgG titer within 2 weeks and maintain the titer for more than 4 months.Compared to the licensed BBIBP-CorV(Sinopharm,China),a single-dose S663V-RBD induced more endurable and robust immune responses in mice and elicited superior neutralizing antibodies against three typical SARS-CoV-2 pseudoviruses including wild type,C.37(Lambda)and B.1.617.2(Delta).More interestingly,the intramuscular injection of S663V-RBD could overcome pre-existing immunity against the capsid.Given its effectiveness,the CASE-based S663VRBD may provide a new solution for the current and next pandemic.

Albumin-based multidrug delivery system enriched in Golgi apparatus against metastatic breast cancer

Breast cancer and metastasis remain great challenges in clinical therapy.Compared with monotherapy,combination therapy,especially mediated by nanomedicine delivery strategy,significantly improves the therapeutic efficacy and reduces undesired toxicity.Cyclooxygenase-2(COX-2)inhibitors are widely used for adjuvant chemotherapy because COX-2 is overexpressed in virtually all cancer cell lines to regulate tumor progression by catalyzing prostaglandin E2(PGE2)synthesis.This drug combination strategy is still required to be improved due to some unsatisfactory clinical trial results.Intricate processes of tumor growth and metastasis are orchestrated by multiple proteins in addition to COX-2,which are modified and transported by Golgi apparatus.Hence,disrupting the structure and function of Golgi apparatus can inhibit the secretion of tumor-related proteins and further suppress carcinoma progression and metastasis.Since COX-2 is also enriched within Golgi apparatus in tumor cells,COX-2 inhibitors and Golgi disrupting agents can be co-delivered to Golgi apparatus to maximize the synergy.In this work,we developed a human serum albumin(HSA)nanoparticle encapsulating pirarubicin(THP),retinoic acid(RA),and indomethacin(IMC),called TIR-HSA,which was observed to be localized in Golgi complex of 4T1 cells.Owing to the synergistic effect of these three drugs,TIR-HSA inhibited the proliferation,migration,and invasion of tumor cells,enhanced the apoptotic rate,and improved the immunosuppressive tumor microenvironment,which remarkably regressed the tumor growth and metastasis and prolonged the survival period of 4T1-bearing mice.