Background and Objective: Extracellular RNA (exRNA) is an evolving concept. In one hand, more endogenous RNA types are detected in various biofluids or found in local extracellular space. These endogenous exRNAs include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), piwi-interacting RNAs (piRNAs), transfer RNAs (tRNAs) and protein-coding messenger RNAs (mRNAs). ExRNA profilings are associated with many physiopathological conditions, including drug resistance in cancer. Endogenous exRNAs are also significantly involved in the molecular mechanisms of cancer drug resistance. In the other hand, exRNA types are expanded to include exogenous RNA therapeutics which started to headline in recent years with the approval of several RNA-based drugs. This review discusses current knowledge of exRNAs function in cancer drug resistance, including their value as biomarkers, the significant roles of modulating cancer drug resistance and the usage of exogenous RNA-based therapeutics to relieve cancer drug resistance.

Methods: The relevant publications, which are covering the exRNAs’ involvement in cancer drug resistance, were searched in the PubMed database and published up to Aug 28, 2022.

Key Content and Findings: Specific RNA profiles in biofluid can work as biomarkers to help test cancer early and reflect clinical status of tumor, which are intrinsic determinants of drug responses in cancer patients. Endogenous exRNAs play roles in multiply aspects regarding drug resistance in cancer. These roles include modulating chemotherapeutic drug transport or efflux, promoting different adaptive responses, maintaining cancer stem cells (CSCs) status and constructing resistance-related tumor microenvironment (TME) as cancers experiencing chemotherapy, or activating immunosuppressive cell lines, inducing immunosuppressive cytokines and interfering with cytotoxic effector immune cells as cancers experiencing immunotherapy. RNA interference (RNAi), antisense oligonucleotides (ASOs) and mRNA based RNA therapeutics have been widely applied to combat drug resistance in cancer treatment, which will be included as one part inside the evolving scope of exRNAs.

Conclusions: ExRNAs profiles are suitable biomarkers to predict drug responses of cancer. Specific exRNA could explain the rise of drug resistance and serve as the target to cure cancer drug resistance. As the special form of exRNA, RNA-based therapeutics can be used to address cancer drug resistance.