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In this paper, a cross-domain integration system composed of a gene transfer technique with a pre-clinical trial, an on-chip circuit design, an off-chip hardware with peripheral unit integration, and a custom software is presented. Opsin protein-gene transfer is successfully conducted to demonstrate that gene transfer treatment with optical stimulation has several benefits compared with electrical treatment. The proposed wireless programmable stimulating system on chip (WPSSoC) is composed of two sensing channels combined with a decimation filter to acquire intracranial electroencephalography (iEEG), an epilepsy detection unit (EDU), a stimulator with a waveform controller, and an ultra-low-power embedded transceiver. The equivalent sample rate of sensed data is 375 samples/s with 16-bit output data. The performance of intermodulation distortion with a third order (IMD3) is approximately 68 dB. The EDU extracts approximate entropy (ApEn) and spectrum bins for the classifier. The stimulator with controller features on the waveform-adjustable function to provide 0-510 μA of electrical stimulation and 0-50 mW of optical stimulation. The proposed transceiver is implemented with a 2.45 GHz on-off keying (OOK) carrier frequency. Transmitter and receiver front-ends perform at 50.6 and 12.7 pJ/bit of energy per bit, respectively. Power consumption and area of WPSSoC are about 1 mW and 13.67 mm2 in a 0.18 μm process, respectively. Circuits of each part are integrated in a 4.3 cm × 2 cm printed circuit board. The shrunk device is verified with Thy1-ChR2-YFP gene transfer in C57BL/6 mice by using a custom software which is used to provide commands and monitor iEEG.