Successful treatment of endodontic and periapical diseases requires the elimination of bacteria and microbial biofilms from root canals. Currently, the most preferred irrigation method involves the delivery of sodium hypochlorite via the combination of a syringe and ultrasonic activation. Calcium hydroxide is the main choice for intracanal medicament between endodontic appointments and treatment. However, conventional chemical disinfection of root canals is controversial due to drug permeability and drug resistance. New small biomolecule formulations with high penetrability and bioremediatory capacity, including antimicrobial peptides such as M33D and LL-37, antisense RNA ASwalR/ASvicR and nanoparticles such as silver nanoparticles, mesoporous calcium-silicate nanoparticles and chitosan nanoparticles, have effective antibacterial and antibiofilm properties for use in root canal systems and dentinal tubules, thereby promoting the healing of apical lesions. However, the in vivo drug stability, biosafety, and cl