biomarkers by extracting ISF and can also be used as electrodes to detect blood glucose, tumor biomarkers and pH value in body fluids in real time.MNs are composed of a series of microsized needles and are widely used in transdermal drug delivery systems (TDDS) due to the advantages of high efficiency, safety and convenience. In recent years, MNs have been frequently used to deliver drugs, genes, proteins, RNAs and vaccines, and have achieved amazing therapeutic effects. [5] Additionally, MNs are also widely studied for blood sampling, signal monitoring and biosensor. [6] The new coronavirus COVID-19 is raging around the world. Researchers had developed a fingertip-sized MNs to deliver the vaccine. The results showed that the vaccine could produce SARS-CoV-2 specific antibodies in mice that could neutralize the virus. [7] Zhou et al. [8] loaded the anticancer drug curcumin into the MNs, and verified the antitumor effects of MNs in the melanoma model. In addition, MNs had also been used in clinical practice, and researchers had evaluated the efficacy and safety of MNs administration based on the effects of clinical trials. The results indicated that MNs showed similar or more efficient results compared with conventional treatment methods. [9] Interstitial fluid (ISF) is an alternative source to detect traditional biomarkers such as blood and urine. [10] Recently, a new method has emerged, that is, using MNs to extract ISF and analyze biomarkers in ISF. [11] The materials for preparing the MNs are usually metals or polymers. The tips length of MNs is about 50-900 µm, which can penetrate the skin stratum corneum to extract ISF. [12] However, ISF has received limited attentions from researchers due to the difficulty of extracting ISF. It is very necessary to develop a minimally invasive technique to sample ISF for clinical monitoring and diagnosis.ISF can be collected by techniques such as micro dialysis or open flow perfusion, these techniques not only require local anesthesia and professional operations but also take a certain amount of time, and there is a potential risk of infection. [13] It is a promising technique to extract ISF by inserting MNs into skin to form micropores. The average depth of the dermis is generally 500-2000 µm. [14] The tips of MNs are generally short, and they can penetrate the superficial layer of the skin but cannot reach the nerves and blood vessels in the dermis, which can painlessly extract ISF. [15] The biggest challenge of extracting ISF for analysis is insufficient sampling, which greatly limits The traditional way of disease diagnosis is to detect biomarkers in serum, blood, urine, and saliva, but it often faces wound infection and pain, and usually requires professional medical personnel to operate, which is unacceptable for most people. As a result, minimally invasive detection of biomarkers has attracted wide attention and is expected to become a new method for patient monitoring and disease diagnosis. Interstitial fluid (ISF) acts as a medium between cells and the circulatory ...