## 1 Introduction  
Therapeutic options now available for hepatocellular carcinoma (HCC) include surgical resection, liver transplant, arterial chemoembolization, and systemic therapy. Unfortunately, all these efforts have not changed the fact that HCC is still one of the most common causes of cancer-related death worldwide. Furthermore, current therapies cannot fully meet clinical needs, especially in late detection and advanced diseases, which so far represent most HCC cases. Compared with traditional clinical methods, nanotechnology has the advantages of high individual selectivity, active targeting ability, and integration of diagnosis and treatment. However, the high-potential nanomedicine still has complex problems to understand and address. It has been realized, for example, that the advantage of long circulation time and passive accumulation of nanosystems covered by a hydrophilic shell by the EPR effect can be lost the moment the nanoparticle is inside the tumor microenvironment; in proximity to the tumor cell surface, the uptake is hampered by the high hydrophilicity and hydration state. This is the so-called PEG dilemma [1]. Stealth and effective uptake are two faces of this \"dilemma\" involving PEG as well as other hydrophilic shell-forming polymers [2] on nanoparticles. An exciting approach to this problem is to use cleavable PEG groups [3]. With this strategy, PEG helps to achieve a long circulation time; however, the layer sheds after extravasation and increases the chance of the cellular uptake, uncovering the less encumbered, less hydrophilic core.  
A better approach to circumvent the low cellular uptake of PEG-conjugated nanoparticles is to install specific moieties at the distal end of the hydrophilic polymer chain to switch the passive targeting (mediated by the EPR effect) to an active targeting approach, mediated by the specific recognition through a hyper-expressed protein on the target cell surface [4]. However, even if the system is, in theory, apparently fixed, a second underestimated dilemma appears after the ligand is installed. Indeed, the ligand itself can trigger unwanted interactions of the nanocarriers with biological components, face the risk of enzymatic degradation and potential immune response, and even promote RES uptake, shortening the circulation to unproductive levels. The consequences null the advantage of having both the hydrophilic shell covering the system and the active targeting agent.  
A specific liver-directed drug delivery system is proposed in the present paper. The new material is a structural analogue to one of the most studied copolymers in the field of nanotechnology for biomedical application: PEG-PLA. Otherwise, the block copolymer is here obtained by the condensation between a phenylboronic acid ended methoxy polyethylene glycol (MeO-PEG\({}_{2000}\)-PBA) and a galactose capped PLA of two different molecular weights, 1-5 kDa (PLA-Gal\({}_{1-5\mathrm{K}}\)) and 5-10 kDa (PLA-Gal\({}_{5\mathrm{-10K}}\)). The resulting amphiphilic co-polymer, MeO-PEG\({}_{2000}\)-PBGal-PLA, is designed to be: (1) able to assemble in an aqueous environment forming nanoparticles/micelles; (2) pH adaptive, as the boronic ester formation is reversible and the equilibrium can be moved towards a de-shielded system in acidic environment. In the tumoral environment, where the pH is lower compared to blood and normal tissues, this would correspond to a selective exposition of Gal ligands in proximity of the target [5]. Moreover, because Gal is recognized by the asialoglycoprotein receptor (ASGPR), which is hyper-expressed on hepatocytes, its anchoring on the surface of nanocarriers has already paved the way for the efficient liver active-targeting approach [6]. Contrarily to what has been reported before, our approach would allow a new ligand presentation strategy in which Gal is together structural element for the stimulus-responsive PEG de-shielding as well as the targeting moiety.