Promoting the Recruitment, Engagement, and Reinvigoration of Effector T Cells via an Injectable Hydrogel with a Supramolecular Binding Capability for Cancer Immunotherapy.

T cells play a basic and key role in immunotherapy against solid tumors, and efficiently recruiting them into neoplastic foci and sustaining long-term effector function are consistent goals that remain a critical challenge. Here, an injectable alginate-based hydrogel with abundant ß-cyclodextrin (ALG-ßCD) sites is developed and intratumorally injected to recruit CCR9+ CD8+ T cells (a subset of T cells with robust antitumor activity) via the trapped chemokine CCL25. In the meantime, an intravenously injected adamantane-decorated anti-PD1 antibody (Ad-aPD1) would hitchhike on recruited CCR9+ CD8+ T cells to achieve the improved intratumoral accumulation of Ad-aPD1. Moreover, the Ad-PD1 and Ad-PDL1 antibodies are immobilized in the ALG-ßCD hydrogel through supramolecular host-guest interactions of Ad and ßCD, which facilitate engagement between CD8+ T cells and tumor cells and reinvigorate CD8+ T cells to avoid exhaustion. Based on this treatment strategy, T cell-mediated anticancer activity is promoted at multiple levels, eventually achieving superior antitumor efficacy in both orthotopic and postsurgical B16-F10 tumor models.

In Situ Programming of Nanovaccines for Lymph Node-Targeted Delivery and Cancer Immunotherapy.

In situ cancer vaccines consisting of antigens and adjuvants are a promising cancer treatment modality; however, the convenient manufacture of vaccines in vivo and their efficient delivery to lymph nodes (LNs) remains a major challenge. Herein, we outline a facile approach to simultaneously achieve the in situ programming of vaccines via two synergetic nanomedicines, Tu-NPFN and Ln-NPR848. Tu-NPFN (∼100 nm) generated a large number of antigens under an alternating magnetic field, and Ln-NPR848 (∼35 nm) encapsulating adjuvant R848 captured a portion of generated antigens for the manufacture of nanovaccines in situ and LN-targeted delivery, which significantly promoted the uptake and maturation of dendritic cells to initiate potent anticancer immune responses. Notably, combined with an anti-CTLA4 antibody (aCTLA-4), this therapy completely eradicated distant tumors in some mice and exerted a long-term immune memory effect on tumor metastasis. This study provides a generalizable strategy for in situ cancer vaccination.

A tumor acidity-driven transformable polymeric nanoassembly with deep tumor penetration and membrane-anchoring capability for targeted photodynamic therapy.

In recent years, directly damaging cell membrane therapeutic modalities have attracted great attention in the field of cancer therapy due to their critical role in guaranteeing essential cellular function. In this study, the transformable nanoassembly PEG-Ce6@PAEMA, consisting of the photosensitizer polyethylene glycol-chlorin-e6 (PEG-Ce6) and tumor pH-sensitive polymer poly(2-azepane ethyl methacrylate) (PAEMA), was developed for highly efficient membrane-targeted photodynamic therapy. The PAEMA core is rapidly protonated at the acidic tumor pH, resulting in the disassembly of PEG-Ce6@PAEMA and regeneration of PEG-Ce6. Subsequently, the resultant PEG-Ce6 with a very small size (~2.6 kDa) ensures deep penetration into tumor tissue and direct and rapid anchoring to the cancer cell membrane, eventually achieving superior tumor growth inhibition under light irradiation. Thus, this tumor acidity-driven transformable polymeric nanoassembly provides a simple but efficient strategy for membrane targeting cancer therapy.

Injectable hydrogel-mediated combination of hyperthermia ablation and photo-enhanced chemotherapy in the NIR-II window for tumor eradication.

Local administration of therapeutic agents with long-term retention capabilities efficiently avoids nonspecific distribution in normal organs with an increased drug concentration in pathological tissue. Herein, we developed an injectable and degradable alginate-calcium (Ca2+) hydrogel for the local administration of corn-like Au/Ag nanorods (NRs) and doxorubicin hydrochloride (DOX·HCl). The immobilized Au/Ag NRs with strong absorbance in the near-infrared II (NIR-II) window efficiently ablated the majority of tumor cells after 1064 nm laser irradiation and triggered the release of DOX to kill residual tumor cells. As a result, injectable hydrogel-mediated NIR-II photothermal therapy (PTT) and chemotherapy efficiently inhibited tumor growth, resulting in the complete eradication of tumors in most of the treated mice. Furthermore, owing to the confinement of the Au/Ag NRs and DOX·HCl within the hydrogel, such treatment exhibited excellent biocompatibility.

Corn-like Au/Ag nanorod-mediated NIR-II photothermal/photodynamic therapy potentiates immune checkpoint antibody efficacy by reprogramming the cold tumor microenvironment.

Immune checkpoint blocking (ICB) antibodies have shown great success in the clinic, but their low response rate in patients with immunosuppressive cold tumors remains a huge challenge. Inspired by the capability of immunogenic cell death (ICD) to convert tumors from cold to hot, we developed a corn-like Au/Ag nanorod (NR) that can induce the ICD of tumor cells under 1064-nm light irradiation. The corn-like Au/Ag NRs plus NIR-II light irradiation strikingly increased the tumor infiltration of T cells and provoked a systemic immune response to reprogram the immunosuppressive cold tumor microenvironment; these NRs synergized with ICB antibodies to efficiently inhibit distant tumor growth. Encouragingly, the combination of aCTLA4 and Au/Ag NRs plus 1064-nm light irradiation elicited a strong immunological memory effect that protected against tumor recurrence.