Environment friendly drug perfusion manifests as a grand problem in tumor remedy [1], [2], [3]. Therapeutic nanoparticles have been demonstrated to build up at tumor tissue, however nonetheless confronted with solely a small fraction (usually lower than 5 %) penetration into the tumour interstitial area usually [4], [5]. Numerous antistromal therapies, reminiscent of degrading extracellular matrix (ECM) parts or reversing stromal cells’ perform to inhibit ECM manufacturing, have emerged to enhance the supply effectivity of nanotherapeutics into tumors [6], [7], [8], [9]. Nonetheless, the penetration effectivity is invariably inadequate for efficient entry to tumors. This brings the pressing want for more practical methods to beat stromal obstacles to reinforce the therapeutic outcomes. Extra importantly, tumor cells are capable of improve environmental H+ counting on the extreme technology of lactic and carbonic acids through exacerbated glycolysis. Such an indicator of tumor has been well known as a set off to stimulate on-demand drug launch for sensible drug supply.
As a sort of desmoplastic and epithelial tumors, salivary adenoid cystic carcinoma (SACC) is a extremely heterogeneous and metastatic tumor, which happens within the salivary glands of head and neck, usually arising from glandular epitheliums and ductal epitheliums [10], [11]. Throughout SACC growth, tumor cells often endure a change from epithelial to mesenchymal phenotype, the so-called epithelial-mesenchymal transition (EMT) course of, endowing tumors with malignant properties, reminiscent of facilitated invasion and dissemination [12]. Of particular observe, partial EMT (p-EMT), by which tumor cells endure incomplete EMT course of with concurrent epithelial and mesenchymal options, has proven extra shut relation with tumor biology and therapeutic resistance than pure EMT [13], [14], [15], [16]. Utilizing single-cell transcriptomic evaluation, Bernstein et al. discovered that tumor cells underwent p-EMT with excessive expression of ECM proteins, which spatially positioned at the forefront of major tumors [17]. These limbic acellular parts would type a dense, cross-linked, pure “sanctuaries” for tumor cells to resist the intrusion of exterior therapeutics, indicating that the vital significance of p-EMT in mediating the formation of formidable barrier for inhibiting nanotherapeutics transportation into interstitial areas of the tumors. Such a p-EMT-based peripheral blockade works as a beforehand neglected physiological barrier for nanotherapeutic penetration. Subsequently, the regulation of p-EMT course of can be a possible technique to interrupt the outermost protecting wall for enhanced drug perfusion, thereby laying a positive basis to enhance therapeutic efficacy.
Noteworthily, reworking development factor-β 1 (TGF-β1) has been recognized as an efficient inducer of p-EMT [17], [18]. TGF-β1 secreted by tumorous or stromal cells exerts a paracrine affect on malignant cells to precise a p-EMT program with elevated ECM proteins [19], [20]. Extra apparently, the modern localized p-EMT cells are discovered to be in shut apposition to surrounding cancer-associated fibroblasts (CAFs), suggesting a posh crosstalk between CAFs and tumor cells in mediating p-EMT [21], [22]. As an essential supply of TGF-β1, CAFs can launch energetic TGF-β1 into the TME to advertise tumor development and development [23], [24]. Aside from TGF-β1, interleukin 6 (IL-6) has been verified largely produced by CAFs and considerably accelerates the EMT development of tumor cells [25], [26]. Though inadequate proof reveals the direct capabilities on p-EMT initiation, IL-6 strongly upregulates the manufacturing of laminins which type the primary construction of p-EMT barrier [27], [28], [29]. On the premise of this, it’s affordable to conceive that blocking CAFs’ perform in producing TGF-β1 and IL-6 might be conducive to inhibiting the transcriptional program of p-EMT, thereby reducing the technology of peripheral proteins of stromal obstacles.
Contemplating these elements, we rationally developed a hybrid cell membrane-camouflaged nanodrug to beat p-EMT-induced stromal obstacles through inhibiting CAFs-produced p-EMT inducers (e.g., TGF-β1 and IL-6) for enhanced tumor-targeted drug perfusion. Particularly, we verified that p-EMT associated proteins clustered across the medical SACC tumor nests, forming compact and steady obstacles. On this regard, a tailored nanodrug was constructed by camouflaging curcumin (CUR)-based, antitumor drug doxorubicin (DOX)-loaded, metal-organic framework (C/D-MOF) with hybrid cell membranes from CAFs and SACC tumor cells, ensuing within the formation of C/D-MOFHM (HM, hybrid membranes from CAFs and SACC cells). As proven in Scheme 1A, CUR, a naturally polyphenolic energetic molecule, was used to inhibit the secretion of TGF-β1 and IL-6 from CAFs [24], [30], which was integrated into zeolitic imidazolate framework-8 (ZIF-8)-like MOF. Of specific significance, the engineered C/D-MOFHM, harnessing homotypic concentrating on skill, might targetedly act on CAFs by the pH-triggered launch of CUR in order to lower intratumoral TGF-β1 and IL-6 ranges to chop off the paracrine interactions in selling p-EMT. As such, the p-EMT-induced technology of limbic ECM protein can be restrained, which was in favor of the next DOX transportation from exterior into the inside of stable tumors for environment friendly tumor cell killing. The deep penetration of the designed C/D-MOFHM nanodrug couldn’t solely dramatically potentiate chemotherapy to suppress the tumor development but additionally inhibit tumor metastasis, offering a promising technique for treating the intractable SACC tumor (Scheme 1B, C).
