Durable protective efficiency provide by mRNA vaccines require robust immune memory to antigens and weak immune memory to lipid nanoparticles.

The Pegylated lipids in lipid nanoparticle (LNPs) vaccines have been found to cause acute hypersensitivity reactions in recipients, and generate -LNPs immunity after repeated administration, thereby reducing vaccine effectiveness. To overcome these challenges, we developed a new type of LNPs vaccine (SAPC-LNPs) which was co-modified with sialic acid (SA) - lipid derivative and cleavable PEG - lipid derivative. This kind of mRNA vaccine can target dendritic cells (DCs) and rapidly escape from early endosomes (EE) and lysosomes with a total endosomal escape rate up to 98 %.

Sialic acid-modified doxorubicin liposomes target tumor-related immune cells to relieve multiple inhibitions of CD8 T cells.

In different types of cancer treatments, cancer-specific T cells are required for effective anticancer immunity, which has a central role in cancer immunotherapy. However, due to the multiple inhibitions of CD8 T cells by tumor-related immune cells, CD8 T-cell mediated antitumor immunotherapy has not achieved breakthrough progress in the treatment of solid tumors. Receptors for sialic acid (SA) are highly expressed in tumor-associated immune cells, so SA-modified nanoparticles are a drug delivery nanoplatform using tumor-associated immune cells as vehicles.

Simultaneous dendritic cells targeting and effective endosomal escape enhance sialic acid-modified mRNA vaccine efficacy and reduce side effects.

mRNA vaccines are attractive prospects for the development of DC-targeted vaccines; however, no clinical success has been realized because, currently, it is difficult to simultaneously achieve DC targeting and efficient endosomal/lysosomal escape. Herein, we developed a sialic acid (SA)-modified mRNA vaccine that simultaneously achieved both. The SA modification promoted DCs uptake of lipid nanoparticles (LNPs) by 2 times, >90% of SA-modified LNPs rapidly escaped from early endosomes (EEs), avoided entering lysosomes, achieved mRNA simultaneously translated in ribosomes distributed in the cytoplasm and endoplasmic reticulum (ER), significantly improved the transfection efficiency of mRNA LNPs in DCs.

Cleavable-Branched Polymer-Modified Liposomes Reduce Accelerated Blood Clearance and Enhance Photothermal Therapy.

In recent years, cationic liposomes have been successfully used as delivery platforms for mRNA vaccines. Poly(ethylene glycol) (PEG)-lipid derivatives are widely used to enhance the stability and reduce the toxicity of cationic liposomes. However, these derivatives are often immunogenic, triggering the rise of anti-PEG antibodies.

A potential platform of combining sialic acid derivative-modified paclitaxel cationic liposomes with antibody-drug conjugates inspires robust tumor-specific immunological memory in solid tumors.

The recent approvals for antibody-drug conjugates (ADCs) in multiple malignancies in the past few years have fueled the ongoing development of this class of drug. However, the limitation of ADCs is selectivity toward cancer cells especially overexpressing the antigen of interest. To broaden the anti-cancer spectrum of ADCs, combinatorial strategies of ADCs with chemotherapy have become a central focus of the current preclinical and clinical research.

Sialic acid-mediated photochemotherapy enhances infiltration of CD8 T cells from tumor-draining lymph nodes into tumors of immunosenescent mice.

Immunoscenescence plays a key role in the initiation and development of tumors. Furthermore, immunoscenescence also impacts drug delivery and cancer therapeutic efficacy. To reduce the impact of immunosenescence on anti-tumor therapy, this experimental plan aimed to use neutrophils with tumor tropism properties to deliver sialic acid (SA)-modified liposomes into the tumor, kill tumor cells SA-mediated photochemotherapy, enhance infiltration of neutrophils into the tumor, induce immunogenic death of tumor cells with chemotherapy, enhance infiltration of CD8 T cells into the tumor-draining lymph nodes and tumors of immunosenescent mice, and achieve SA-mediated photochemotherapy.

Targeting of TAMs with freeze-dried monosialotetrahexosylganglioside and sialic acid-octadecylamine co-modified liposomes remodels the tumor microenvironment and enhances anti-tumor activity.

Although anti-tumor strategies targeting tumor-associated immune cells were being rapidly developed, the preparations were usually limited in targeting efficiency. To overcome this barrier, this study reported a novel sialic acid-octadecylamine (SA-ODA) and monosialotetrahexosylganglioside (GM1) co-modified epirubicin liposomes (5-5-SAGL-EPI), which improved tumor-targeting ability through the active targeting of tumor-associated macrophages (TAMs) by SA-ODA and the long circulation of GM1. Thus, we evaluated 5-5-SAGL-EPI in vitro and in vivo.

Optimization design of sialic acid derivatives enhances the performance of liposomes for modulating immunosuppressive tumor microenvironments.

Aims: Sialic acid derivatives (SA-derivatives) provide a nanomedicine platform for tumor-targeted delivery and treatment, and allow modulation of immunosuppressive tumor microenvironments with excellent therapeutic effects. Further, the multi-reactive groups of sialic acid (SA) contribute to the diversity of SA derivatives, which inevitably has implications for drug delivery systems and tumor therapy. However, relevant research remains lacking at present.

An Application of Tumor-Associated Macrophages as Immunotherapy Targets: Sialic Acid-Modified EPI-Loaded Liposomes Inhibit Breast Cancer Metastasis.

Breast cancer metastasis is an important cause of death in patients with breast cancer and is closely related to circulating tumor cells (CTCs) and the metastatic microenvironment. As the most infiltrating immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs), which highly express sialic acid (SA) receptor (Siglec-1), are closely linked to tumor progression and metastasis. Furthermore, the surface of CTCs also highly expressed receptor (Selectin) for SA.

Antitumor Immunotherapy of Sialic Acid and/or GM1 Modified Coenzyme Q10 Submicron Emulsion.

Immunotherapy is a novel therapeutic approach for controlling and killing tumor cells by stimulating or reconstituting the immune system, among which T cells serve as immune targets. Herein, we used coenzyme Q10 (CoQ10), which has both immune activation and avoids adverse reactions, as a model drug and developed four CoQ10 submicron emulsions modified with sialic acid (SA) and/or monosialotetrahexosyl ganglioside (GM1). On the one hand, SA interacts with L-selectins on the surface of T cells after entering the circulatory system, leading to activation of T cells and enhancement of antitumor immune responses.

The Fate of Sialic Acid and PEG Modified Epirubicin Liposomes in Aged versus Young Cells and Tumor Mice Models.

In preclinical studies of young mice, nanoparticles showed excellent anti-tumor therapeutic effects by harnessing Peripheral Blood Monocytes (PBMs) and evading the immune system. However, the changes of age will inevitably affect PBMs and the immune system, and there is a serious lack of relevant research. Sialic acid (SA)-octadecylamine (ODA) was synthesized, and SA- or polyethylene glycol (PEG)-modified epirubicin (EPI) liposomes (EPI-SL and EPI-PL, respectively) were prepared to explore differences in antitumor treatment using 8-month-old and 8-week-old Kunming mice.

Sialic acid conjugate-modified liposomes enable tumor homing of epirubicin via neutrophil/monocyte infiltration for tumor therapy.

Neutrophils and monocytes (N/Ms) are potential candidates for the delivery of therapeutic agents to the tumor microenvironment (TME) because of their tumor-accumulating nature. L-selectin and Siglec-1, receptors for sialic acid (SA), are highly expressed in circulating neutrophils and monocytes, respectively, in tumor-bearing mice, and N/Ms are recruited to tumors in response to inflammatory cytokines secreted by the TME, promoting tumor growth and invasion. Therefore, we constructed a drug delivery nano-platform using N/Ms as vehicles.

Sequential administration of sialic acid-modified liposomes as carriers for epirubicin and zoledronate elicit stronger antitumor effects with reduced toxicity.

Combined administration of drugs can improve efficacy and reduce toxicity; therefore, this combination approach has become a routine method in cancer therapy. The main combination regimens are sequential, mixed (also termed "cocktail"), and co-loaded; however, other combinations, such as administration of synergistic drugs and the use of formulations with different mechanisms of action, may exert better therapeutic effects. Tumor-associated macrophages (TAMs) play functional roles throughout tumor progression and exhibit characteristic phenotypic plasticity.