Programmed antigen capture-harnessed dendritic cells by margination-hitchhiking lung delivery

Cancer immunotherapy boosts the immune system and primes T cells to recognize and fight cancer cells, potentially suppressing tumors and inducing immune memory [1,2]. Despite recent advances in immunotherapy, the poor vascularization and low presence of tumor-associated antigens at metastases of numerous invading clusters (usually smaller than <100 mm3) deteriorates the plight of weakening physical contact between T cells and cancer cells at the early metastasis stage [[3], [4], [5]]. Furthermore, immune privilege arises from the recognition of T cells by cancer cells, leading to the escape of T cell attacks [6,7].

To overcome this obstacle, a simple strategy is to collect functional reagents in target organs and then guide cancer cell apoptosis to release secondary tumor antigens and promote T cell induction. In this regard, a neovascular-targeted delivery system exhibits accumulation in early metastases, but clinically low tumor suppression is attributed to the accumulation of stromal thylakoids [[8], [9], [10]]. Another approach is to engineer functional agents onto a specific cell to hitchhike into the target organ [[11], [12], [13]]. For example, RBC can squeeze through capillaries with a much narrower diameter and recover their original shape rapidly owing to their flexibility [14,15]; thus, therapeutic agents, such as liposomes or pro-drugs [16,17], can be transferred to lung metastasis via RBC hitchhiking [18,19]. Besides that, due to the feature of RBC, it can be supplied for drug delivery as their natural lung targetability. As documented in the literatures, RBCs squeezed through the lung capillaries and transferred cargo to pulmonary capillary endothelial cells [[20], [21], [22]]. Furthermore, cell-hitchhiking drug-carrying particles enhance nanoparticle delivery capabilities (e.g., targeting and circulation) and increase their efficacy in clinical trials, while reducing toxic side effects [23,24]. RBC are ideal candidates to meet all the requirements of drug delivery systems, such as prolongation of systemic circulation time, are endogenous cells with high biocompatibility and low immunogenicity [[25], [26], [27], [28]].

In addition to targeting, immune regulation and tumor infiltrating lymphocytes are important issues in metastatic immunotherapy [[29], [30], [31]]. Magnetic hyperthermia via iron oxide nanoparticles (IO) involves destruction of tumors by localized heating up to 41–46 °C, which leads to the killing of cancer cells or permanent cell damage via apoptotic or necrotic pathways [[32], [33], [34], [35], [36]]. Efficient apoptosis or necrosis can activate tumor-associated antigens and promote the recruitment of T cells [[37], [38], [39], [40], [41], [42]]. In particular, IO has been reported as an antigen carrier and adjuvant [[43], [44], [45]], both of which promote efficient antigen presentation and antigen-specific approaches to activate downstream immune processes [46,47].

Here, a multi-grained iron oxide nanostructures (MIO) assembled onto RBC ([email protected]) that combines the features of RBC hitchhiking and immunomodulator was developed for lung metastasis targeting and hyperthermia at tumor (Fig. 1a). After hitchhiking to the lung, MIO penetrates into lung metastases through uptake by alveolar luminal endothelial cells and leukocytes, which then absorb energy and cause cancer cell apoptosis (Fig. 1b). As it exhibits multi-domains of magnetic crystalline, the frictional heat on MIOs can be generated by an alternating magnetic field (AFM) via the magnetic spin flipping (Néel relaxation) and particle rotation (Brownian relaxation) at moderate intensity and operating frequency. In tumors, induced heat further causes cancer to invoke apoptosis to release tumor-associated antigens. In addition, MIO acts as an antigen capture agent to deliver neoantigens and damage-associated molecular patterns to lymph nodes, contributing to efficient T cell recruitment and immunotherapy (Fig. 1b). The large amount of MIOs disrupts the cell-cell interactions at tumor, actuating T cell infiltration. The versatile [email protected] is an outstanding immune modulator for improving immune response at lung metastases and activating T cells. In addition to RBC hitchhiking strategy for iron oxide nanoparticles to lung, the innovations of this study are as follows. (1) The multiple domains of the MIO can generate intense heat remotely through an alternating magnetic field (AFM). (2) MIO acts as an antigen capture agent to deliver neoantigens and damage-associated molecular patterns to lymph nodes. (3) Intercellular interactions at the tumor may be disrupted, promoting T cell infiltration. The multifunctional M[email protected] is an excellent immunomodulator that improves the immune response and activates T cells in lung metastases.

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