People in Malaysia prefer to use traditional medicine before modern medicine is introduced. A complete report on the Malay traditional medicinal plants was compiled in a book, entitled “A Dictionary of the Economic Products of the Malay Peninsula”. This book has inspired both phytochemists and ethno-botanists to conduct research on medicinal plants, which helps add knowledge to Malaysian medicinal plants (R. Renuka et al., 2001, Al-Sokanee et al., 2009). F. deltoidea and G.sublanceolata leaves are used as traditional medicine. These plants are used to treat various sickness and diseases. Malaysia is famous for F.deltoidea called “Mas Cotek”. This plant belongs to Moraceae family. F.deltoidea leaves have two kinds: female and male. Female leaves have higher active ingredients, so this kind of leaves are used for medical purposes compared to male ones. Hail of Rubiaceae family includes G. Sublanceolata leaves called Pitang. These leaves turn brown when they are dry. It is very difficult to find these leaves because they are very rare; however, we can find a huge number of these plants in Thailand. These plants have a diversity of Pigments, namely xanthophyll, chlorophyll, flavonol, flavones, carotene and anthocyanin (Mucalo et al., 2004). The biochemical ingredient of the plants has a significant role as the natural antioxidants and the activity of the extracted plant polymers is higher when they consumed as crude and the combination of different extracts (R. Renuka et al., 2001). However, the major disadvantage is that the quantity of herbal extract necessary for the treatment is higher because the degradation of different plant compounds such as alkaloids, flavonoids, phenols, steroids, and anthraquinon in the gastrointestinal tract. It is due to the acidic pH in the stomach, which increase their breakdown, loss of the effect and increment with the duration of treatment with the decreased absorption of these compounds in the intestine (Al-Sokanee et al., 2009 ). Currently, several researchers and studies are concentrated on encapsulation/capping of the plant extracts to increase the sustained release of active compounds in the intestine for the maximal absorption (Mucalo et al., 2004, Hench et al., 1991, Ivone 2001, Kavitha et al., 2017, Walum et al., 1998, Yehya et al., 2019, Gopinath et al. 2016). Recently, nanotechnological methods have activated the advanced delivery systems, which include the controlled drug delivery to the site of action by developing hydroxyapatite and other nanoparticles (Anniebell and Gopinath, 2018, Suk et al., 2018. Hydroxyapatite [Ca10(PO4)6(OH)2] (HAp), is the main constituents of bone and teeth, a biomaterial in view of its excellent bioactivity, biocompatibility, non-toxicity and non-inflammatory. HAp nanoparticles can be prepared by the direct precipitation method possess the advanced important characteristics such as, large pore volumes, high surface area and reactive surfaces for post-functionalization and pure powder which make them ideal as potential carriers for the plant extract as drugs (Cao et al., 2014). Moreover, it has also been confirmed that HAp nanoparticles with the size lesser than 100 nm could be up taken by the cells efficiently. The biocompatibility and bioactivity of HAp nanoparticles represent a choice for the controlled drug delivery (Matouskova et al., 2016). Using nanotechnology with phyto-extracts has explored a beneficial strategy for herbal drugs including the enhancement of bioavailability, bioavailability, solubility, sustained delivery pharmacological activity, physical and chemical degradation and protection from toxicity (Arunachalam et al., 2017, Theivasanthi et al., 2018). This is the first study were conducted on the ingestion of these encapsulated combine of plant extract with nanoHAp at high doses. Therefore, there is a need to explore the systemic for evaluating their efficacy and safety properties. Hence, this study aims to evaluate the safety of this extract with acute and sub-chronic toxicity tests in BALB/c mice model.