2-methyltetrahydrofuran (2-MeTHF) is a readily available, inexpensive, neoteric, bio-based solvent. It has been adopted across a wide range of chemical processes including the batch manufacture of fine chemicals, enzymatic polycondensations and ring opening polymerizations. To reduce the environmental burden related to the synthesis of pharmaceutical-grade polymers based on lactide and caprolactone, we envisaged the use of 2-MeTHF. For the first time, we combined a series of metal-free and enzymatic ROPs with free radical and controlled RAFT polymerizations (carried out separately and in tandem) in 2-MeTHF, in order to easily tune the chemistry and the architecture of the final polymers. After a simple purification, the amphiphilic polymers were formulated into nanoparticles and tested for their cytocompatibility in three model cell lines, to assess their application as potential polymeric excipients for nanomedicines. K E Y W O R D S2-MeTHF, green solvent, organo-enzymatic ROP, ROP-free radical tandem polymerizations, ROP-RAFT tandem polymerizations

Functional ring‐opening polymerization (ROP) initiators can instill a wide array of chemical, physical, and biological effects into a polymeric chain. Highlighting the versatility of this “active” initiator approach, a broad range of characteristics can be achieved through the use of initiators with chemistries spanning from drugs and dyes (key in the case of drug delivery or nanoparticle applications) through to radically active monomers, polymerization transfer agents, and catalysts. The selection of a suitable “active” initiator (monomers for tandem reactions, dyes, drugs, stereo‐catalysts, etc.) can not only provide the final polymers with interesting application potential but also facilitate the implementation of ROP reactions in tandem with other polymerization techniques. Overall, this review will highlight that functionalities and properties can be effectively tuned by exploiting simple chemistry approaches, allowing readers to identify how these approaches could be of benefit to their own work in a range of applications including drug/gene delivery, amphiphilic bio/degradable carriers, drug/scent controlled release, and stereo‐controlled polymers.

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