RNA interference (RNAi) has been emerged as an effective method to silence a particular gene utilizing a sequence‐specific mechanism for gene regulation. It induces target mRNA degradation leading to a lower illness‐inducing gene product. RNAi represent a conserved mechanism. Novel concept of highly specific silencing of genes was revolutionized by the introduction of short interfering RNA (siRNA).This helped to overcome the drawbacks of RNAi and proved out to be a safer and efficient method than its counterpart finding its way into the pharmaceutical industry. Clinical trials enhanced the possibility of siRNA delivery and yielded promising results for the treatment of a wide range of illnesses but mainly for intractable diseases like cancer, inflammatory diseases, and genetic disorders. siRNA delivery methods were instrumental in developing it as a therapeutic, of which lipid encapsulation crept its way, to be a better in vivo delivery mechanism as it could be formulated effectively, being biodegradable, and has a lower toxicity level. However, the therapeutic potential of siRNA remains hampered due to a lack of a viable delivery method, a lower accuracy in tissue specificityand cytotoxicity. Hence the therapeutic usage of the method is in its budding stage. This review re‐examines the principle of siRNA, challenges in its delivery, and some recent advancesto overcome the obstacles in order to improve siRNA delivery.

siRNA interference is a conserved cellular gene silencing mechanism and a viable technique for human disease intervention, including cancer. This method has significant potential benefits over currently available treatments. The limitations of using siRNA‐based systems are the lack of specificity, high chance of degradation, toxicity, and ineffective cellular uptake. Combination therapy using natural compounds possesses higher therapeutical value with siRNA. Various natural compounds are used in cancer treatments such as paclitaxel, ursolic acid, hypericin, etoposide, etc due to their diverse bioactivities. In this review, the codelivery of natural compounds/siRNA using nanovehicles is highlighted.