Inhibition of post-surgery tumour recurrence via a sprayable chemo-immunotherapy gel releasing PD-L1 antibody and platelet-derived small EVs

Abstract

Background Melanoma is the most serious type of skin cancer, and surgery is an effective method to treat melanoma. Unfortunately, local residual micro-infiltrated tumour cells and systemic circulating tumour cells (CTCs) are significant causes of treatment failure, leading to tumour recurrence and metastasis. Methods Small EVs were isolated from platelets by differential centrifugation, and doxorubicin-loaded small EVs (PexD) was prepared by mixing small EVs with doxorubicin (DOX). PexD and an anti-PD-L1 monoclonal antibody (aPD-L1) were co-encapsulated in fibrin gel. The synergistic antitumour efficacy of the gel containing PexD and aPD-L1 was assessed both in vitro and in vivo. Results Herein, we developed an in situ-formed bioresponsive gel combined with chemoimmunotherapeutic agents as a drug reservoir that could effectively inhibit both local tumour recurrence and tumour metastasis. In comparison with a DOX solution, PexD could better bind to tumour cells, induce more tumour immunogenic cell death (ICD) and promote a stronger antitumour immune response. PexD could enter the blood circulation through damaged blood vessels to track and eliminate CTCs. The concurrent release of aPD-L1 at the tumour site could impair the PD-1/PD-L1 pathway and restore the tumour-killing effect of cytotoxic T cells. This chemoimmunotherapeutic strategy triggered relatively strong T cell immune responses, significantly improving the tumour immune microenvironment. Conclusion Our findings indicated that the immunotherapeutic fibrin gel could “awaken” the host innate immune system to inhibit both local tumour recurrence post-surgery and metastatic potential, thus, it could serve as a promising approach to prevent tumour recurrence. Graphical Abstract

Platelet-Inspired Nanotherapeutics for Biomedical Applications

“…Apart from mimicking platelet and modulating platelet functions, the applications of platelet derivatives have received increasing attention in recent years. For example, small extracellular vesicles released by activated platelets can participate in some specific physiological and pathological processes. − Furthermore, platelet-derived polyphosphates can be used as procoagulants to control hemorrhage. − In this section, the potential nanotherapeutics driven by platelet derivatives will be discussed, including mainly two aspects: (i) platelet extracellular vesicle-derived nanotherapeutics and (ii) platelet polyphosphate-based nanotherapeutics.…”

“…Moreover, platelet-derived EVs might reduce TNF-α and IL-8 production, thereby suppressing inflammation . Due to their unique features, various functions and ease of clinical translation, platelet EVs as nanocarriers loaded with functional cargoes hold considerable promise mainly for (i) cancer cell adhesion and (ii) inflammation regulation. − …”

Nanomaterials: small particles show huge possibilities for cancer immunotherapy

“…Immunotherapy combined with chemotherapy is considered a reliable treatment option, but improving its bioavailability and targeting is the key to achieving efficient treatment [ 251 , 252 ]. Sun et al [ 253 ] proposed a dual-lumen nano hydrogel spray to inhibit postoperative tumor recurrence and metastasis by reviving the body's immune system. Tube A has fibrin and α-PD-L1, and tube B is thrombin and PexD, a platelet-derived extracellular vesicle (Pex) loaded with DOX.…”

Sprayable hydrogel for biomedical applications

“…5). 156 It was observed that PexD activity could improve the combination with tumor cells, prompt further immunogenic tumor cell death and stimulate a more intense anti-tumor immune response compared with DOX solution. Furthermore, the sprayable immunotherapeutic fibrin gel could activate the host's innate immune system, thus inhibiting the potential of local melanoma recurrence and metastasis post-surgery.…”