Single cell analysis provides nuanced insights into biological systems. Combinatorial barcoding enables scalable scRNA-seq with high sensitivity and flexible inputs but is difficult with fewer than 100,000 cells. We developed a modified fixation and capture method for low-cell-number inputs that is fully compatible with this approach. Our method allows researchers to fix, store, and barcode up to 384 samples in parallel without costly instruments. Fixed samples remain stable at -80℃, support automated barcoding, and achieve high capture efficiency with as few as 10,000 cells. This streamlined workflow improves consistency, minimizes error, and maximizes recovery, enabling accurate profiling of transcriptional changes from perturbations. As proof-of-concept, we screened cancer drug and histone modification panels with 10,000–20,000 cells per treatment. Robust capture preserved gene detection during perturbation, while Evercode WT transcriptome profiling revealed drug- and cell-type–specific responses. The results validate drug targets, identify off-target effects, and demonstrate how low-input fixation combined with combinatorial barcoding enables high-throughput cancer and epigenetic compound screening.
