LDH-mediated autophagic full-chain blockade for Multiple Myeloma treatment by targeting circ_0008255/miR-192-5p/ATG2A axis.

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy with limited therapeutic options. Although autophagy dysregulation is implicated in MM pathogenesis, its precise regulation, particularly by circular RNAs (circRNAs), is poorly understood. Through clinical RNA sequencing of primary MM patient samples, we identify an autophagy-associated circRNA, circ_0008255, which is markedly upregulated in MM patients and closely correlated with poor disease prognosis. Functional studies reveal that circ_0008255 promotes MM proliferation and tumor growth by enhancing autophagic activity. Mechanistically, it functions as a competitive endogenous RNA for miR-192-5p, leading to elevated expression of the core autophagy protein, autophagy related 2 homolog A (ATG2A). Furthermore, we developed a biomimetic nanoplatform based on layered double hydroxide (LDH) nanosheets coated with myeloma-derived cell membranes for tumor-specific delivery. This system co-delivers siRNA targeting circ_0008255 to suppress autophagosome initiation, while simultaneously leveraging the lysosome-alkalinizing property of LDH to impair autophagosome-lysosome fusion. Together, these actions enforce a synergistic autophagic full-chain blockade, leading to potent antitumor effects in vitro and in vivo. Overall, our study reveals a central regulatory role of circ_0008255 in myeloma autophagy, offering a promising therapeutic paradigm for MM.