## 4 Conclusions  
Overcoming the \"PEG dilemma\", prolonging nanosystem blood circulation, and enhancing their tumor accumulation appears an urgent need in nanomedicine and personalized medicine. Preventing cellular uptake and endosomal escape processes is particularly important for drug targeting hepatocytes. Although active targeting can improve the uptake in a specific cell/tissue, it is not always a solution for the dilemma, but it requires the ligand to be appropriately presented. The best scenario would be the one in which PEG detachment and ligand presentation are concerted and do not depend on different physical phenomena characterized each by their own kinetic and pH sensibility. The strategy proposed in this research is the development of a liver targeted drug delivery system where the block condensation, the stimulo-responsiveness for hydrophilic shell loss, and the active targeting ligand presentation coexist in a unique element. This is a pH-reversible boronic ester formed between a Gal and a PBA residues at the core-shell interface. During the research, we successfully settled a synthetic pathway leading to MeO-PEG\({}_{2000}\)-PBA and PLA-Gal of two different Mws in order to explore a broader applicability. Overall, the study confirms the presence of a functional free boronic acid end-cap on the PEG derivative and shows the ability of MeO-PEG-PBA to form a pH adaptive boronic ester with Gal, efficiently targeting hepatocytes, being recognized by the ASGPR receptor since asialoglycoprotein is hyper-expressed on hepatocytes' membrane. It shows also that the formation of the two blocks should occur in a basic environment to maximize the yield of the hydrophilic corona installation. The obtained preliminary results encourage us to move towards a future perspective of exploring the best conditions, which enable the preservation of the integrity of the polyester and the use of a suitable base, in aqueous or organic medium. Light should be also shed on the kinetic stability of the construct: being the bond at the interface between the hydrophobic core and the hydrophilic shell, it is likely that this would influence the dissociation of the blocks, the rate at which the PEG dissociates at pH 7.4 from the nanoparticle surface. Finally, the work represents the proof of concept for our approach suggesting an alternative way of thinking about active targeting and the ligand presentation strategy. The following supporting information can be downloaded at: [[https://www.mdpi.com/article/10.3390/app12094225/s1](https://www.mdpi.com/article/10.3390/app12094225/s1)]([https://www.mdpi.com/article/10.3390/app12094225/s1](https://www.mdpi.com/article/10.3390/app12094225/s1)), Figure S1: ATR FTIR spectrum of MeO-PEG\({}_{2000}\)-PBA-Pin; Figure S2: ATR FTIR spectrum of MeO-PEG\({}_{2000}\)-PBA; Figure S3: ATR FTIR spectrum of PLA-Alk; Figure S4: ATR FTIR spectrum of PLA-Gal; Figure S5: Characteristics of PEG derivatives and their weighted distribution of MW obtained by GPC. A: MeO-PEG\({}_{2000}\); B: MeO-PEG\({}_{2000}\)-PBAPin; C: MeO-PEG\({}_{2000}\)-PBA; Figure S6: Characteristics of PLA-COOH and their GPC traces; Figure S7: Calibration of the GPC system; Paragraph: Analytical methods used for the calculation of binding constants (comprise Figures S8 and S9 and Equations (S1)-(S6). Reference [16] is cited in the supplementary materials. **Author Contributions:** All authors have contributed substantially to the work reported. Conceptualization, C.S. ; methodology, C.S. and G.A. ; investigation, C.T. ; data curation, writing--original draft preparation, review and editing, T.E. ; G.A., R.P.A. and C.S. ; funding acquisition, R.P.A. All authors have read and agreed to the published version of the manuscript. **Funding:** The research was supported by Regione Campania Italy--\"Combattee la resistenza tumorale: piattaforma integrata multidisciplinare per un approrecio tecnologico innovativo alle onocterapie\"-P.O.R. Campania FESR 2014-2020-B61G18000470007-Codice progotto: 300390 PORON-COTERAPIE.